MLN9708 May be Alternative to Bortezomib in Multiple Myeloma

Shaji K. Kumar, MD

An investigational proteasome inhibitor known as MLN9708 has shown comparable efficacy and greater convenience and tolerability than a standard drug in its class, bortezomib, for patients with multiple myeloma (MM), investigators have found.

Shaji K. Kumar, MD, of the Mayo Clinic in Minnesota, announced the findings at the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH).

In a phase I/II study, MLN9708 was combined with immunomodulatory agent lenalidomide and a steroid, dexamethasone, and given to adult patients with previously untreated MM. Their response rates were consistent with those of MM patients who received, in previous trials, the combination of bortezomib, lenalidomide, and dexamethasone, a standard treatment for high-risk MM patients, Kumar said.

While that standard is one of the most effective regimens for MM, bortezomib must be administered via injection and carries a risk of nerve damage—specifically, peripheral neuropathy—which can deter patient adherence to treatment, Kumar said. Thus MLN9708, which is orally administered, may offer a more convenient and tolerable form of therapy that limits the risk of nerve damage, he said.

In order to assess the efficacy, safety, and proper dose of MLN9708 in the target population, researchers enrolled 65 patients and treated them for up to a year in monthly cycles that each included three weekly doses of MLN9708, four weekly doses of dexamethasone, and 21 days of lenalidomide, followed by maintenance therapy with MLN9708 three times a month until disease progression or toxicity.

Primary objectives in phase I included safety, maximum tolerated dose, and recommended phase II dose. In phase II, using a recommended dose of 4 mg, primary objectives included complete remission and very good partial response (VGPR), measured by a 90% or greater reduction in abnormal myeloma proteins in the blood.

According to preliminary phase II results, investigators recorded an overall response rate of 92% with the drug combination. Fifty-five percent of patients reached VGPR or better, including 23% who experienced complete remission. As the treatment cycles progressed, the rate and depth of response increased.

Minor adverse events, such as fatigue, nausea, and rash, were noted in approximately 40% of patients, Kumar and his co-authors wrote in the paper presented at ASH. Thirty-two percent of patients reported neuropathy, in most cases grade 1. Serious adverse events were minimal and primarily consisted of decreased blood counts, nausea and vomiting, diarrhea, rash, and electrolyte disturbances. One patient died from pneumonia while on treatment, and seven patients discontinued treatment due to different side effects.

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“With the combination of MLN9708, lenalidomide, and dexamethasone, the improvements are convenience; that the combination appears to be less toxic; and that it appears to have at least the same efficacy as we would have expected,” Kumar said. “That will translate into patients being able to stay on it longer-term, which might give more benefits than what we have seen with some other previous therapies. All of this must be confirmed in phase III studies before we consider it a standard of practice, but I have high hopes.”

A phase III clinical trial of MLN9708 will test the same three-drug combination in the relapsed setting versus a pairing of lenalidomide and dexamethasone, Kumar said, and a separate phase III trial will test MLN9708 with lenalidomide and dexamethasone, again, in newly diagnosed patients. Other combinations are being explored, the doctor added, including that of MLN9708 with cyclophosphamide and dexamethasone.

Also reported at ASH were the results of a phase I study of MLN9708 in patients with relapsed or refractory systemic light-chain amyloidosis.

“Preliminary evidence of hematologic responses and early organ responses in this heavily pretreated population are encouraging,” said Karen Ferrante, MD, chief medical officer for the drug’s developer, Millenium.

References

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 (MM). Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 332.

Merlini G, Sanchorawala V, Zonder JA, et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 731.

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