Encouraging Phase II Data for All-Oral First-Line Regimen in Newly Diagnosed Multiple Myeloma

An investigational, weekly, oral proteosome inhibitor called MLN9708 achieved excellent response rates when combined with lenalidomide and dexamethasone as up-front treatment of newly diagnosed patients with multiple myeloma, according to results of a phase II trial presented at the 54th Annual Meeting of the American Society of Hematology. If these results are verified in phase III trials, then patients with multiple myeloma will have an all-oral regimen available for first-line treatment.

“The all-oral combination of MLN9708, lenalidomide, and dexamethasone is well tolerated with limited neuropathy. The regimen is very active, and responses increased with number of cycles and deepened over time,” stated lead author Shaji K. Kumar, MD, Department of Hematology, Mayo Clinic, Rochester, MN.

Dr Kumar said that the all-oral regimen will be compared with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma in a phase III trial currently enrolling patients; another phase III trial of this regimen in previously untreated patients is in the planning stages.

“This is the first oral proteosome inhibitor and it is distinct from bortezomib, with a favorable toxicity profile showing low rates of peripheral neuropathy,” he continued.

For the phase II study, MLN9708 was combined with lenalidomide/dexamethasone, one of the most common regimens uses for newly diagnosed multiple myeloma patients. The goal was to develop an all-oral regimen that was safe and effective, he said.

A phase I study of 15 patients, conducted by Dr Kumar et al, identified the maximum tolerated dose of 2.97 mg/m² for the investigational agent. The phase II trial included 50 patients treated with the 3-drug regimen using MLN9708 at a fixed dose of 4 mg/week (equivalent of 2.23 mg/m²), standard lenalidomide, and dexamethasone 40 mg on days 1, 8, 15, and 22. Patients were treated with up to 12 cycles every 3 weeks for a 4-week cycle. MLN 9708 maintenance was administered on days 1, 8, and 15 every 28 days. Treatment was continued until disease progression or toxicity.

Twenty-three of the phase II patients (46%) were still on treatment at the time of the ASH annual meeting. Stem cells were successfully collected at the end of 3 cycles in all 20 patients in whom it was attempted.

Overall, at least a very good partial response (>VGPR) was achieved in 58% of patients—after 4 cycles, >VGPR was 49%; after 8 cycles, >VGPR was 58%; and after 12 cycles, >VGPR was 100%.

“The likelihood of response increased over time,” Dr Kumar said.

Neuropathy of all grades was reported in 21 patients (34%) and it was mainly mild (20%). Grade 2 neuropathy was observed in 9% and grade 3 in 3%. The most common adverse events were skin rash, fatigue, nausea, vomiting, and diarrhea. Serious adverse events occurred in approximately 20% and were mainly gastrointestinal, Dr Kumar noted. Side effects were manageable with dose modifications and supportive care, he added.

Dr Kumar and co-investigators will continue to analyze these data to determine response in subgroups, particularly high-risk patients.

“The new regimen improves convenience and tolerability. We want to see if we can change the natural history of the disease,” he stated.