ASH: Proteasome Inhibitor MLN9708 Shows Promise in Multiple Myeloma

Preliminary findings suggest a “favorable emerging clinical profile” for once weekly administration of MLN9708 in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma, according to Shaji K. Kumar, MD, of the hematology division at the Mayo Clinic, Rochester, Minnesota. Results of the phase I/II multicenter study were presented at the 2012 annual meeting of the American Society of Hematology (ASH).

Chemical structure of MLN9708

The previously reported phase I portion of the study was a dose-escalation study to determine the safety, maximum tolerated dose (MTD) and recommended phase II dose of MLN9708 in combination with standard-dose lenalidomide and dexamethasone. Primary objectives of the ongoing phase II portion are to determine the combined complete and very good partial response rates (≥VGPR), as well as safety and tolerability. Secondary objectives include overall response rate, time to response, duration of response, and progression-free survival.

In this early report Dr. Kumar reported that 53 newly diagnosed multiple myeloma patients received a median of 7 cycles of therapy (range 1–19) at the recommended phase II dose of 4 mg. The overall response rate was 90% and the study has already met its primary endpoint, with 58% of patients achieving ≥VGPR. Three patients completed 12 cycles, two of whom achieved a complete response and one who had a VGPR.

Minimal residual disease was assessed in eight patients who had a complete response and found negative in seven (88%). At data cutoff, 50 of 52 responders remained in response, with responses durable for up to 13.2-plus months. Median time to first response was 0.92 months (range 0.89–6.44). The study is ongoing and patients will continue to be followed to further evaluate the primary and secondary endpoints.

“The MLN9708-based combination evaluated in this study of newly diagnosed myeloma patients, suggests a favorable emerging clinical profile,” said Dr Kumar. “The preliminary findings of improved depth of response with extended treatment duration warrant further investigation of this all-oral combination in frontline myeloma.”

The investigators said the high response rates that have been achieved with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen highlight the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma. MLN9708, the first oral proteasome inhibitor to enter clinical trials, exhibits “promising anti-MM effects and has a favorable toxicity profile with low rates of peripheral neuropathy.”

MLN9708 is also being investigated for treatment of various other hematologic malignancies and solid tumors. Data from a phase I study investigating once weekly administration of MLN9708 in patients with relapsed or refractory systemic light-chain (AL) amyloidosis was reported by Giampaolo Merlini, MD, of the Amyloidosis Research and Treatment Center, University of Pavia, Pavia, Italy.

The primary objectives of this open-label, dose-escalation study were to determine the safety, tolerability, and MTD of MLN9708. Once the MTD was reached, two expansion cohorts were enrolled, one with proteasome inhibitor-naive patients (n=5) and one with proteasome inhibitor-exposed patients (n=12). Fifteen of 17 patients treated at the MTD of 4 mg were evaluable for response (received at least one cycle of treatment and had a response assessment). Two patients experienced a complete response, five patients had a VGPR, and one had a partial response (PR). Duration of response of up to 14.7 months has been reported to date. Median number of cycles was 3 (range 1–12). Three patients experienced disease progression by the end of cycle 1. Eight patients remain on treatment.

“These data suggest weekly oral administration of MLN9708 is feasible in patients with relapsed or refractory AL,” said Dr Merlini. Assessment is ongoing, with preliminary evidence of hematologic responses noted.

Two global phase III trials, one to investigate MLN9708 in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma, and one to investigate MLN9708 plus dexamethasone in patients with relapsed or refractory light chain AL amyloidosis were initiated in 2012.

MLN9078 is being developed by Millennium Pharmaceuticals, a biopharmaceutical company based in Cambridge, Massachusetts, and acquired by Takeda in 2008.