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First Oral Proteasome Inhibitor Active in Myeloma

August 2012 Vol 5, No 5, Special Issue ASCO 2012 Payers' Perspective - Multiple Myeloma

Chicago, IL—The first oral proteasome inhibitor to enter clinical investigation in multiple myeloma is MLN9708. The data from a phase 1 clinical trial presented at ASCO 2012 suggest that this drug encourages disease control and durability of re­sponses in heavily pretreated patients with multiple myeloma.

MLN9708 is a potent, reversible, and specific inhibitor of the 20S proteasome that is similar to bortezomib in structure but is associated with less neurotoxicity, said lead investigator Sagar Lonial, MD, Professor and Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology of Winship Cancer Institute at Emory University, Atlanta, GA.

“MLN9708 is well tolerated, with infrequent peripheral neuropathy and none that is grade 3 or higher,” Dr Lonial said.

This study of twice-weekly dosing of the oral agent included 58 patients who had received multiple prior lines of therapy. The primary aim was to assess tolerability and to determine the optimal dose.

“Unlike many other trials, patients received no concomitant cortico­steroids. This is a pure proteasome inhibitor trial,” Dr Lonial noted.

Of the 53 evaluable patients, 6 achieved a partial response or better, including 1 confirmed stringent complete response in the proteasome inhibitor–naive expansion cohort. “Many of these responses are quite durable,” Dr Lonial said.

Disease stabilization was observed in another 32 patients, and a number of these are in the relapsed and refractory cohorts, he added.

The most common drug-related events were fatigue (45%) and thrombocytopenia (41%). Nausea (36%), vomiting (26%), rash (28%), and diarrhea (21%) were also observed.

“We saw the typical sawtooth curve of thrombocytopenia that we see with bortezomib. You see that the baseline platelet count increases among re­sponses, and it is not cumulative,” Dr Lonial observed.

“A major difference between this drug and bortezomib is that peripheral neuropathy is significantly lower, 10%,” Dr Lonial said. “My longest patient on study had developed grade 3 neuropathy on bortezomib and has been responding to MLN9708 with no neuropathy for over a year now.”

Discontinuations resulting from adverse events were required in 12% of patients, predominantly because of thrombocytopenia, pulmonary hy­pertension, pneumonia, orthostatic hypotension, and pruritic rash, as well as spinal cord compression and bone pain as a result of progressive disease.

Irene Ghobrial, MD, medical staff member in the Myeloma Program of the Dana Farber Cancer Institute, and Associate Professor of Medicine, Har­vard Medical School, Boston, discussed the findings for the MLN9708 study at the multiple myeloma oral session.

“In this population of heavily pretreated patients given MLN9708 as a single agent, the overall response rate was 11%; 2 patients also had a minimal response, and many had stable disease. This is the first oral proteasome inhibitor to be tested. We are now looking at second-generation agents showing activity and less neuropathy and potentially greater convenience. We know if we take these upfront and put them in combination with im­muno­modulatory drugs and steroids, we will see higher responses,” she said.—CH

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Last modified: August 30, 2012
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