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Marizomib May Be Effective In Relapsed / Refractory Multiple Myeloma (ASH 2011)

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Published: Jan 23, 2012 2:33 pm

Combined data from two recent Phase 1 clinical trials suggest that twice-weekly marizomib, with or without low-dose dexamethasone, may be effective for patients with relapsed or refractory multiple myeloma.

Dr. David Vesole from the John Theurer Cancer Center in Hackensack, New Jersey, who was not involved in the study, described marizomib as having “modest activity in relapsed/refractory myeloma.”

Dr. Paul Richardson from the Dana-Farber Cancer Institute in Boston presented the results at the American Society of Hematology (ASH) annual meeting in San Diego last month.

Marizomib (NPI-0052), which is being developed by the company Nereus Pharmaceuticals, belongs to the same class of drugs as Velcade (bortezomib), called proteasome inhibitors.  These compounds prevent the breakdown of important proteins in cancerous cells, thereby causing cell death.

Two other compounds in the same class of drugs are being developed for the treatment of myeloma and have shown promising results: carfilzomib (Kyprolis), which is furthest along in clinical development, and MLN9708 (ixazomib), which, like marizomib, is still in the early phases of clinical development (see related Beacon news).

When asked how marizomib compares to the other drugs in its class, Dr. Vesole said, “Given the small number of patients treated [in the marizomib study], it is not possible to compare the efficacy of this agent … with bortezomib [Velcade] or carfilzomib.”

However, he added, “The efficacy of MLN9708 as a single agent is also quite modest in relapsed/refractory patients. In combination with lenalidomide [Revlimid] and dexamethasone, the agent [MLN9708] appears to be promising in the frontline setting.”

In previous preclinical studies, marizomib showed promising results in myeloma cells that are resistant to Velcade and thalidomide (Thalomid).

The results Dr. Richardson presented were combined data from U.S. and Australian Phase 1 studies of marizomib. The purpose of both studies was to determine the maximum tolerated dose of marizomib, both alone and in combination with dexamethasone (Decadron).

At the time of data analysis, 44 patients had participated in the U.S.study and 25 patients had participated in the Australian trial.

The median patient age was 62.5 years, and the participants had received a median of six prior therapies. Of the 69 patients, 71 percent had prior exposure to Velcade, and 41percent were resistant to treatment with Velcade.

The participants received 0.075 mg/m2 to 0.6 mg/m2 marizomib as an infusion over a period of 1 to 120 minutes on days 1, 4, 8, and 11 of a 21-day treatment cycle. In one study, 20 mg dexamethasone was given the day before and on the day of treatment. In the other study, patients who did not achieve at least a minimal response after two treatment cycles could also receive dexamethasone.

Of the patients evaluable for response, 19 percent achieved at least a partial response and 38 percent achieved stable disease.

The response rate was higher (29 percent) in patients who were resistant to Revlimid (lenalidomide), compared to patients who previously had received Velcade (16 percent) or were resistant to Velcade (17 percent).

Patients responded for a median of five months.

The maximum tolerated dose was established to be 0.5 mg/m2 infused over 120 minutes. Dose-limiting side effects included hallucinations, loss of balance, and cognitive changes, which were all reversible.

Other common drug-related side effects included fatigue, nausea, vomiting, dizziness, headache, diarrhea, constipation, insomnia, weight loss, and shortness of breath.

Dr. Vesole pointed out that marizomib’s side effect profile was different than those observed with Velcade and carfilzomib, especially some transient cognitive changes.

Additionally, the researchers did not observe any of the typical Velcade-related side effects, such as peripheral neuropathy (a condition characterized by pain and tingling in the extremities due to nerve damage) or low platelet counts.

According to Dr. Richardson, twice-weekly 0.5 mg/m2 marizomib, with or without dexamethasone, will undergo continued investigations. Additional follow-up studies will include marizomib in combination with Revlimid and dexamethasone.

For more information, please see abstract 302 on the ASH meeting website and Dr. Richardson’s slide deck, which he has made available as a courtesy to The Beacon’s readers.

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