Novel Agent Marizomib Demonstrates Promising Activity in Relapsed/Refractory Multiple Myeloma

Marizomib (NPI-0052), a novel proteasome inhibitor, decreased the amount of myeloma protein and was well tolerated in patients with relapsed/refractory multiple myeloma (MM), according to preliminary results of a phase I dose-escalation study presented at the 15th International Myeloma Workshop. There were no dose-limiting toxicities observed at any of the four doses treated.

“Nearly all patients with relapsed and refractory multiple myeloma will eventually relapse on currently available therapies, underscoring the importance of developing new treatment options,” said Prof. Andrew Spencer, head of the Malignant Hematology & Stem Cell Transplantation Service at The Alfred Hospital and Professor of Hematology at Monash University in Melbourne, Australia, who presented the results. “Marizomib potently inhibits the three proteolytic activities of the 20S proteasome with specificity and activity distinct from that of bortezomib and carfilzomib.” By irreversibly binding to and inhibiting all three proteasome subunits, he and co-authors explained, the activity translates into longer duration of effect and potentially improved clinical activity.

Dr. Spencer and researchers enrolled 14 patients (median age = 61 years; range = 31-69 years) into the 3 + 3 dose-escalation section of the study. All patients had received two or more prior therapies (including both lenalidomide and bortezomib), and had been refractory to their last therapy. Treatment was administered over 28-day cycles as follows:

  • Marizomib – 0.3-0.5 mg/m2 delivered intravenously over 120 minutes on days 1, 4, 8, and 11
  • Pomalidomide – 3 or 4 mg once daily on days 1 through 21
  • Dexamethasone – 10 mg once daily on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, and 23 of every 28-day cycle

Safety, pharmacokinetics, proteasome inhibition, and clinical response were assessed.

Five patients (36%) had high-risk cytogenetics, and all patients were treated with a median of 4.5 prior therapies (range=2-15). In addition to receiving prior bortezomib and lenalidomide, 50 percent also had received prior carfilzomib.

The most common marizomib-related adverse events included: fatigue (5 patients), neutropenia (5), thrombocytopenia (3), anemia (3), and nausea (2).

One patient experienced tumor lysis syndrome (grade 2), and one patient had increased peripheral neuropathy (grade 1) related to pomalidomide. In addition, one patient came off the study and subsequently died from progressive disease.

All patients had a decrease in myeloma protein by the end of their first treatment cycle.

Of the 11 patients with response data through the third cycle of treatment, the researchers found that, according to International Myeloma Working Group criteria: six patients (54%) achieved partial response, two (12%) experienced a minimal response, and three (27%) achieved stable disease.

“Marizomib 0.4 mg/m2 caused near complete inhibition of the C-TL subunit as early as day 11 of the first treatment cycle, with significant inhibition of the T-L and C-L subunits evolving over time in whole blood assays performed in all patients to date,” Prof. Spencer and colleagues wrote.

“Marizomib does not appear to add toxicity to the established pomalidomide/dexamethasone safety profile, and the combination of drugs demonstrated encouraging activity in some of the sickest patients with multiple myeloma,” Prof. Spencer added during his presentation. “I believe that this combination of drugs holds great promise for the treatment of multiple myeloma.”

As no dose-limiting toxicity was observed in the preliminary results of this study, a dose-expansion stage of the study is planned and will enroll 22 additional patients who will receive marizomib (0.5 mg/m2), pomalidomide (4 mg), and dexamethasone (10 mg).


Reference

Spencer A, Spencer A, Badros A, et al. Phase 1, multicenter, open-label, dose-escalation, combination study (NCT02103335) of pomalidomide (POM), marizomib (MRZ, NPI-0052), and dexamethasone (DEX) in patients with relapsed and refractory multiple myeloma (MM); study NPI-0052-107 preliminary results. Abstract OP-005. Presented at the 15th International Myeloma Workshop, September 25, 2015; Rome, Italy.

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