Oral Proteasome Inhibitor May Be a Game-changer in Myeloma


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An investigational oral proteasome inhibitor currently known as MLN9708 could make the treatment of multiple myeloma much more convenient and possibly less neurotoxic, according to the results of a phase I/II study of treatment-naive multiple myeloma patients presented at the 54th Annual Meeting of the American Society of Hematology.1

MLN9708, given in combination with the immunomodulatory agent lenalidomide (Revlimid), achieved an overall response rate exceeding 90%, with complete responses seen in approximately one-quarter of patients, according to Shaji K. Kumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota.

“There is increasing attention toward developing highly effective regimens that at the same time will be better tolerated, more convenient, and able to be taken for a long time,” Dr. Kumar said. The thought is that combining an oral proteasome inhibitor that carries less risk for peripheral neurotoxicity with an oral immunomodulatory agent might achieve this.

First Oral Proteasome Inhibitor

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

MLN9708 is the first oral proteasome inhibitor to enter clinical trials in myeloma, and it appears to be less neurotoxic than its predecessor, bortezomib (Velcade). When given intravenously twice a week, bortezomib is associated with an overall rate of neuropathy of about 30%, though the new subcutaneous formulation is associated with about half the risk of this side effect. With MLN9708, severe neuropathy is generally seen in fewer than 5% of patients.

With MLN9708, “the peripheral neuropathy signal has been fairly low, compared with what we expect with bortezomib-based regimens, and the oral delivery of the treatment makes a lot of difference to patients in terms of quality of life.” Dr. Kumar said.

First-line Setting

“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. The similar combination of bortezomib plus lenalidomide/dexamethasone is a very effective regimen, he noted. 

The first phase of the study established the recommended phase II dose of the drug (4.0 mg weekly) in 15 patients. Another 50 patients were recruited to evaluate the efficacy of MLN9708 at 4.0 mg weekly (days 1, 8, and 15) in combination with lenalidomide (25 mg/d on days 1–21) and dexamethasone (40 mg/d on days 1, 8, 15, and 22) with the treatment continued for a maximum of 12 cycles. MLN9708 was then continued as maintenance therapy until disease progression. In the 20 patients who wished to undergo an autologous stem cell transplant, stem cells were successfully collected.

Overall, 52 patients were evaluable for response after a median of six cycles of treatment; 58% of them achieved at least a very good partial response, including 23% with a complete response, and 32% achieved a partial response.

The depth of response deepened with increasing exposure to treatment. After eight cycles, the complete response rate was 32%. In the three patients who completed all 12 cycles, 100% of patients achieved at least a very good partial response.

“We are fairly confident that with increased duration, we will see further improvement in the response numbers,” he said, adding that many patients responded after only one cycle of the regimen.

Additional Data

Dr. Kumar further reported that 100% of patients had a reduction in M-protein levels, and almost all patients with a complete response were negative for minimal residual disease.

Though follow-up time is short, an estimated 93% of patients remain free of disease progression at 1 year, he added. “The number of patients at risk beyond 1 year is very low, and the data need to mature,” he cautioned.

Twenty-one patients (32%) reported neuropathy, which was grade 1 in the majority (20%), grade 2 in 9%, and grade 3 in 3%. “Note that grade 3 and higher peripheral neuropathy was very low,” he said. 

About 40% of patients reported minor rash, fatigue, nausea, vomiting, and diarrhea, which were managed with dose reductions and supportive care. Grade 4 events were observed in just four patients.

MLN9708 has entered a phase III trial in multiple myeloma, and two additional trials are planned in newly diagnosed and in relapsed/refractory patients.

Effective in Amyloidosis

The oral proteasome inhibitor MLN9708 also showed strong activity in the first-line treatment of patients with relapsed or refractory systemic light-chain amyloidosis, investigators reported at the ASH meeting.2

To date, this phase I study has enrolled 22 patients, 17 at the maximum tolerated dose of 4.0 mg and 5 at 5.5 mg. A total of 15 patients received at least one cycle and were evaluable for response. Of these, 2 patients achieved a complete response, 5 achieved at least a very good partial response, and 1 demonstrated a partial response to the drug.

Hematologic response durations of up to 14.7 months were observed, and there were three cardiac organ responses among nine evaluable patients, reported Giampaolo Merlini, MD, Director of the Center for Research and Treatment of Systemic Amyloidosis, and of the Biotechnology Research Laboratories, Scientific Institute Policlinico San Matteo, and Professor of Clinical Biochemistry, University of Pavia, Italy.

The phase III TOURMALINE-ALI is ongoing in newly diagnosed amyloidosis patients. ■

Disclosure: Dr. Kumar reported no potential conflicts of interest.

References

1. Kumar SK, Berdeja JG, Niesvizky R, et al: A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma. 2012 ASH Annual Meeting. Abstract 332. Presented December 10, 2012.

2. Merlini G, Sanchorawala V, Zonder JA, et al: MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis: Results of a phase I study. 2012 ASH Annual Meeting. Abstract 731. Presented December 10, 2012.


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Antonio Palumbo, MD, Chief of the Myeloma Unit at the University of Torino in Italy, told The ASCO Post that the results with MLN9708 “look quite interesting,” and the drug could change the treatment of the disease.

“This combination, with lenalidomide, accelerates response, and the ability to...


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