Oral Proteasome Inhibitor MLN9708 a News Maker at ASH 2012

February 2013 Vol 6, No 1, Special Issue - Multiple Myeloma
Caroline Helwick

Atlanta, GA—MLN9708, an investigational oral proteasome inhibitor, produced impressive results in a phase 1/2 clinical trial of treatment-naïve patients with multiple myeloma that was featured in a press briefing at the 2012 American Society of Hematology (ASH) meeting.

Used in combination with lenalidomide, MLN9708 achieved an overall response rate exceeding 90%, and complete responses were seen in 25% of patients, reported Shaji K. Kumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, MN.

“There is increasing attention toward developing highly effective regimens that at the same time will be better tolerated, convenient, and able to be taken for a long time,” Dr Kumar said.

As an oral proteasome inhibitor with a good tolerability profile, MLN9708 may help achieve this goal. It is the first oral drug among the proteasome inhibitors to enter clinical trials with patients with myeloma, which offers a convenient and tolerable treatment regimen. The incidence of peripheral neuropathy with this oral formulation is less than is seen with bortezomib.

The twice-weekly intravenous form of bortezomib is associated with an overall rate of neuropathy of approximately 30%; however, the subcutaneous formulation offers a much reduced incidence, with approximately 10% to 15% neuropathy, Dr Kumar said.

“The peripheral neuropathy signal has been fairly low [with the oral drug] compared with what we expect with bortezomib-based regimens,” Dr Kumar said. He added that besides the good tolerability, MLN9708 represents a huge treatment advance by providing an oral therapy option.  
MLN9708 Studied with First-Line Combination Regimen 

“Given the activity and toxicity profile of MLN9708, we wanted to explore the feasibility and efficacy of combining MLN9708 with lenalidomide and dexamethasone,” Dr Kumar said. This mirrors the highly effective combination of the similar drug bortezomib plus lenalidomide and dexamethasone combination.

“The goal was to develop a highly effective, safe, and convenient, all-oral regimen for the initial treatment of myeloma,” he said.

After establishing the maximum tolerated dose of the drug, 65 patients were evaluated in the study, in which MLN9708 was given on days 1, 8, and 15 in combination with lenalidomide (25 mg daily on days 1-21) and with dexamethasone (40 mg on days 1, 8, 15, and 22). MLN9708 was then continued as maintenance therapy for up to 12 cycles. In the 20 patients who were to undergo an autologous stem-cell transplant, stem cells were successfully collected.

Overall, 52 patients were evaluable for response after a median of 6 cycles of treatment; of these patients, 58% achieved at least a very good partial response (≥VGPR), 32% achieved a partial response, and 23% had a complete response.

The depth of response deepened with increasing exposure to treatment. After 8 cycles, the complete response rate was 32%, and in the 3 patients who completed all 12 cycles, 100% of patients achieved ≥VGPR.

“While the follow-up is still very short, progression-free survival is 93%,” Dr Kumar added. “The number of patients at risk beyond 1 year is very low, but the data need to mature.”

Twenty-one patients (32%) reported neuropathy, which was grade 1 in 20% of patients, grade 2 in only 9%, and grade 3 in 3% of patients. Mild rash, fatigue, nausea, vomiting, and diarrhea were reported by 40% of patients. These were well managed with dose reductions and supportive care, Dr Kumar said.

Two serious adverse events (grade 4) were observed, including end-stage renal disease in 1 patient (resulting from disease progression) and deep-vein thrombosis in 1 patient. In addition, 1 patient died from pneumonia while receiving treatment.

In light of the promising results seen with MLN9708, the drug has entered a phase 3 trial, and 2 other trials are planned in newly diagnosed patients with myeloma and in those with relapsed and/or refractory disease.

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