Oral Proteasome Inhibitors Advancing in Multiple Myeloma Trials


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Ravi Vij, MD

Shaji K. Kumar, MD

Our preliminary data suggest that step-up dosing [with oprozomib] is associated with improved tolerability, with fewer gastrointestinal adverse events observed and less hematologic toxicity, though the numbers are small.

—Ravi Vij, MD
Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience.

—Shaji K. Kumar, MD

Two orally administered proteasome inhibitors—oprozomib and ixazomib—looked encouraging in multiple myeloma studies presented at the 2014 ASH Annual Meeting and Exposition.

Study Details for Oprozomib

Oprozomib, given as a single agent in a dose-escalation study of heavily pretreated patients, “showed promising antitumor activity,” which included responses even in patients with carfilzomib (Kyprolis)-refractory disease,1 according to Ravi Vij, MD, of Washington University in St. Louis. Oprozomib binds selectively and irreversibly to its target, resulting in sustained inhibition.

Dr. Vij presented data from an ongoing multicenter open-label phase Ib/II study of 129 patients with hematologic malignancies, including 87 with relapsed and/or refractory disease. “The majority of patients had seen bortezomib [Velcade] and carfilzomib, and quite a few were refractory to both these drugs,” Dr. Vij noted.

Patients received oprozomib in various schedules and dose levels in 2-week blocks. The formulation of oprozomib was changed during phase Ib of the study, from powder-in-capsule to extended-release tablet, and in phase II, step-up dosing was introduced. These amendments appeared to improve the drug’s tolerability.

In the phase Ib cohort receiving 150 to 330 mg/d for 2 of every 7 days (2/7 schedule), the objective response rate was 31.3%, and the clinical benefit rate was 50%. In the phase Ib/II patients who received 150 to 270 mg/d for 5 of 14 days (5/14 schedule), the response rate was 23.3%, and the clinical benefit rate was 32.6%.

Of note, these response rates were observed before the step-up dosing schedule was initiated. Response data were not presented for the step-up cohorts due to limited treatment exposure (approximately 7 weeks). Interestingly, responses were achieved by 18.2% of carfilzomib-refractory patients in this study, he added.

Step-Up Dosing

The recommended phase II dose and schedules were the 2/7 step-up schedule at 240/300 mg/d and the 5/14 step-up schedule at 150/180 mg/d.

In the cohorts evaluated before the benefit of step-up dosing, the most common grade ≥ 3 nonhematologic adverse events were diarrhea, nausea, and vomiting. With step-up dosing, these events were less common, he said.

In the 240/300 mg/d step-up cohorts in phase II, grade ≥ 3 nausea and diarrhea were observed in only 10% each. Similarly, hematologic toxicities grade ≥ 3 were limited to anemia (11%) in the 240/300 mg/d cohort and neutropenia (10%) in the 150/180 mg/d cohort.

Treatment-emergent peripheral neuropathy was rare, occurring in five patients (6%), only one being grade 3. Rash was observed in 6 patients (7%), and none was ≥ grade 3. There were three deaths in the 5/14 dosing cohort before step-up dosing was instituted: Two were due to upper gastrointestinal bleeding, and one was due to disease progression.

“Our preliminary data suggest that step-up dosing is associated with improved tolerability, with fewer gastrointestinal adverse events observed and less hematologic toxicity, though the numbers are small,” Dr. Vij reported. “With the phase II step-up dose of 150/180 mg/d, we have seen no grade 3 gastrointestinal toxicity. There’s also a hint that dose reductions and discontinuations for adverse events are less.”

Enrollment on the 2/7 and 5/14 schedules of the extended-release tablet is continuing. Target enrollment for the phase II portion for the myeloma cohort is 94 patients. 

Maintenance Ixazomib

Data from a phase I/II clinical trial support further evaluation of the investigational, oral, proteasome inhibitor ixazomib in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of newly diagnosed multiple myeloma and alone as maintenance therapy.2

Shaji K. Kumar, MD, of the Mayo Clinic, Rochester, reported the results of a study of 65 newly diagnosed patients. Of them, 25 entered the maintenance phase and were the subject of this analysis. They received a median of 31 total cycles (induction and maintenance) with 19 being maintenance cycles.

Maintenance with ixazomib improved the depth of response after induction. The overall response rate in this study was 90%; complete responses were observed in 22% after induction but increased to 52% by the end of maintenance, Dr. Kumar reported.  

“With maintenance, we saw a deepening of response in 48% of patients,” he noted. The rate of complete responses plus near complete responses increased from 24% after induction to 62%, with 71% rated very good partial responses or better. Ixazomib maintenance contributed to durable responses.

Half the patients were still on maintenance therapy at the time of the report. The estimated percentage of patients surviving without disease progression at 2 years was 57%. Serious adverse events were observed in four patients (19%) during ixazomib maintenance, none of which were considered related to treatment.

Ixazomib is the first oral proteasome inhibitor and has physiochemical properties distinct from bortezomib. The triplet of bortezomib/lenalidomide/dexamethasone has produced high response rates, and it has become increasingly clear that extended treatment (ie, maintenance therapy) may add benefit to conventional induction strategies, he indicated.

“Agents for continuous therapy, however, need to be convenient and well tolerated,” Dr. Kumar suggested. “Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience.”

“Single-agent ixazomib maintenance for up to 1.9 years was feasible, with a generally manageable safety profile, in patients not undergoing autologous stem cell transplant,” he said. New-onset toxicity during single-agent ixazomib maintenance was rare. Only 2 of 21 patients required dose reductions during maintenance, and there were no treatment discontinuations due to adverse events and no on-study deaths.

Phase III trials of ixazomib are underway in both newly diagnosed and relapsed cohorts. ■

Disclosure:  Dr. Vij has received honoraria from Celgene, Onyx Pharmaceuticals, Sanofi, Janssen Pharmaceuticals, Novartis, Millennium, and Array BioPharma and research funding from Celgene and Onyx Pharmaceuticals. Dr. Kumar has served as a consultant to and received research funding from Celgene, Millennium, Onyx Pharmaceuticals, Sanofi-Aventis, Array BioPharma, and Janssen Pharmaceuticals and is on the Board of Directors or advisory committees of Skyline Diagnostics.

References

1. Vij R, et al: Clinical profile of single-agent oprozomib in patients with multiple myeloma. 2014 ASH Annual Meeting. Abstract 34. Presented December 6, 2014.

2. Kumar S, et al: Long-term ixazomib maintenance is tolerable and improves depth of response following ixazomib-lenalidomide-dexamethasone induction in patients with previously untreated multiple myeloma. 2014 ASH Annual Meeting. Abstract 82. Presented December 7, 2014.

 



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