Phase 1/2 Trial of MLN9708 for Multiple Myeloma

Atlanta—Patients with previously untreated multiple myeloma, who took the investigational agent MLN9708 in combination with lenalidomide and dexamethasone, responded well to the drug regimen and tolerated the treatment, according to a phase 1/2 trial.

Of the patients enrolled, 92% had a partial response or better, including 55% with a very good partial response or better and 23% achieving complete remission. The median time to response was one cycle, while the median duration of response had not been reached.

Shaji K. Kumar, MD, the study’s lead author and professor and consultant at the Mayo Clinic in Rochester, Minnesota, presented the results in an oral abstract session at the ASH meeting. He said investigators are currently enrolling patients with relapsed and/or refractory multiple myeloma for a phase 3 trial comparing MLN9708 in combination with lenalidomide and dexamethasone with placebo plus lenalidomide and dexamethasone.

Millennium Pharmaceuticals, Inc. (The Takeda Oncology Company), the manufacturer of MLN9708, funded the study.

Dr. Kumar said the treatment for multiple myeloma has “dramatically changed” in the past decade. The introduction of proteasome inhibitors and immunomodulatory drugs has led to patients living longer and having a better quality of life.

MLN9708 is the first oral proteasome inhibitor in clinical development to treat multiple myeloma. In an earlier study, preliminary data showed clinical activity associated with heavily pretreated multiple myeloma patients who took MLN9708 monotherapy weekly or twice weekly, according to Dr. Kumar.

This trial included patients ≥18 years of age who had not received treatment for multiple myeolma and had an Eastern Cooperative Oncology Group performance status score of 0, 1, or 2, adequate hepatic, renal, and hematologic function, and measurable disease. Patients were excluded if they had grade 2 or higher peripheral neuropathy or a prior or concurrent deep vein thrombosis or pulmonary embolism.

Patients received MLN9708 on days 1, 8, and 15 of a 28-day treatment cycle plus 25 mg of lenalidomide daily on days 1 through 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22. They took as many as 12 cycles and then received maintenance therapy with MLN9708 on the same schedule until experiencing disease progression or unacceptable toxicity.

The authors allowed stem cell collection after 3 cycles and had autologous stem cell transplantation deferred until after 6 cycles. The protocol also called for mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin.

The phase 1 trial included 15 patients who were enrolled between November 2010 and October 2011: 3 patients took 1.68 mg/m² of MLN9708 weekly, 3 received 2.23 mg/m² weekly doses, 6 received 2.97 mg/m² weekly doses, and 3 took 3.95 mg/m² weekly doses.

The phase 2 study enrolled 50 patients between October 2011 and February 2012. The recommended dose was 2.23 mg/m² weekly, which was later increased to 4.0 mg/m² weekly after results indicated patients were tolerating the drug.

Patient characteristics were similar in the phase 1 and 2 studies. Median age was 66 years, and 55% were males. They took a median of 6 cycles of therapy. As of the October 17, 2012 data cutoff date, 42% of patients remained on treatment, with the most common reasons for stopping cited as proceeding to an autologous stem cell transplant (31%), experiencing an adverse event (12%), or having progressive disease (5%).

Grade 3 or higher adverse events were found in 66% of patients, 37% had a serious adverse event, and 43% reduced their dosage after experiencing an adverse event. The most common grade 3 adverse events were neutropenia, anemia, thrombocytopenia, skin rash, and vomiting. In addition, 32% of patients had treatment-emergent peripheral neuropathy, although 13 of the 21 patients had grade 1 and only 2 had grade 3.

One patient who received 4.0 mg/m² of MLN9708 died during the study after having respiratory syncytial virus following cycle 4, which Dr. Kumar said was possibly related to treatment or the underlying disease state. Seven other patients discontinued the study after experiencing an adverse event, with 4 due to treatment-related adverse events.