Proteasome Inhibitor May Benefit Difficult-to-Treat Myeloma Patients

A new, investigational proteasome inhibitor, oprozomib (Onyx Pharmaceuticals, Inc.), has shown activity in multiple myeloma, including those patients with carfilzomib-refractory disease.

About one-quarter of the patients--in two different dosing cohorts--responded to treatment and about one-third derived clinical benefit from the treatment. These results were presented at the American Society of Hematology annual meeting by Ravi Vij, MD, of Washington University in St. Louis.

The trial enrolled advanced hematological malignancy patients, including 68 with multiple myeloma. Two dosing schedules, with administration of the drug for 4 and 5 days total within a 14-day cycle, were tested. The so-called "5/14" cohort administered oprozomib on days 1 through 5 of the 14-day cycle.

In one dosing cohort of 15 patients, the overall objective response was 33.3%. The clinical benefit rate was 46.7%, including three very good partial responses, two partial responses, and two patients with minimal responses. Of the 19 patients in the second dosing cohort--all of whom were carfilzomib-naïve--the overall objective response was 36.8%. The clinical benefit rate was 42.1% including one complete response, two very good partial responses, four partial responses, and one minimal response. Among the seven patients who were bortezomib refractory in this cohort, the overall response rate was 14.3%.

In the phase 2 portion of the trial, the overall response among the 11 carfilzomib-refractory patients was 27.3% (3 partial responses). Among the 12 patients who were carfilzomib sensitive, the overall response was 33.3% (two very good responses and two partial responses). The response rate among the 12 bortezomib-refractory patients was 25%.

Oprozomib has been tested as a single-agent for other hematologic cancers, and this phase Ib/II study continues to evaluate patients with other hematologic cancers as well as multiple myeloma.

Median treatment duration was 21.3 weeks in the 2/7 dosing cohort and 10.1 weeks in the 5/14 dosing cohorts. The maximum tolerated dose was 240 mg per day in the 5/14 cohort.  

Dose-limiting toxicities in the 5/14 cohort were two patients with Grade 3 renal failure at the 180 mg per day dose and one Grade 3 tumor lysis syndrome at the 270 mg per day dose. The most common hematologic adverse events were anemia and thrombocytopenia. Common non-hematologic adverse events were nausea, vomiting, diarrhea, decreased appetite, and fatigue.

Grade 4 adverse events included thrombocytopenia in eight patients (11.8%), four patients with anemia (5.9%), and one patient (1.5%) each with leukopenia, sepsis, and decreased platelet count.

In the 5/14 dosing schedule group, three patients in the phase 1b cohort (15%) and eight (30%) in the phase 2 cohort discontinued treatment due to an adverse event. Seven patients (35%) in the phase 1b cohort and 11 patients (41%) in the phase 2 cohort had their doses reduced at least once due to an adverse event.

Severe gastrointestinal (GI) toxicities were reported and two patients died of upper GI bleeding. According to the study presentation, modifying the dose schedule to a step-up dosing regimen improved tolerability to oprozomib. An extended-release formulation is currently being evaluated.

According to the study abstract, further measures will be taken to improve the GI tolerability to oprozomib. Oprozomib, as a single-agent is promising for its antitumor activity among multiple myeloma patients, the study authors conclude.