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MLN9708 Shows Encouraging Results For The Treatment Of Multiple Myeloma (ASCO 2012)

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Published: Jun 15, 2012 9:48 am

Interim results from three clinical trials suggest that MLN9708, as a single agent or in com­bi­na­tion with Revlimid and dexa­meth­a­sone, may be an effective and well tolerated treat­ment for both pre­vi­ously untreated multiple myeloma patients and patients with re­lapsed or refractory disease.

Findings from the three trials were presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago earlier this month.

According to Dr. Irene Ghobrial from the Dana Farber Cancer Institute in Boston, who presented a review of some of the MLN9708 results at ASCO, the response rates from these early trials investigating MLN9708 (ixazomib) as single-agent ther­apy in re­lapsed and refractory myeloma patients “are 6 per­cent to 13 per­cent, but we know that if we take [MLN9708] into upfront studies, and we put it in com­bi­na­tion with immunomodulators [such as Revlimid] and steroids, we will have higher responses.”

She added that MLN9708 may also have potential as a main­te­nance treat­ment after initial ther­apy for myeloma, and as a treat­ment for smol­der­ing myeloma.

MLN9708 is an orally admin­istered proteasome inhibitor in the same class of drugs as Velcade (bor­tez­o­mib) and carfilzomib (Kyprolis). Initial results of the three trials had pre­vi­ously shown that treat­ment with MLN9708 leads to high response rates and low rates of periph­eral neu­rop­athy, a con­di­tion char­ac­ter­ized by pain and tingling in the extremities.

Twice Weekly MLN9708 As A Single-Agent Treatment

Dr. Sagar Lonial of the Emory Winship Cancer Institute presented the results of a Phase 1 study investigating the efficacy and safety of twice-weekly MLN9708 as a single-agent treat­ment in re­lapsed and refractory multiple myeloma patients.

The study included 58 patients with a median age of 65 years. Patients had received a median of four prior treat­ments, including prior Velcade (90 per­cent of patients), Revlimid (lena­lido­mide) (88 per­cent), thalidomide (Thalomid) (62 per­cent), and car­filz­o­mib (13 per­cent). Over half of the patients (56 per­cent) had received a stem cell trans­plant. The median time since diag­nosis among the patients was 4.8 years.

“This is a relatively heavily pre-treated re­lapsed/refractory patient population,” said Dr. Lonial.

Patients received between 0.24 mg/m2 and 2.23 mg/m2 of MLN9708 on days 1, 4, 8, and 11 of a 21-day treat­ment cycle.

Patients have received a median of four treat­ment cycles, and 17 per­cent have received more than 12 cycles.

Of the 53 evaluable patients, 12 per­cent have responded so far, with 2 per­cent reaching a complete response, 4 per­cent a very good partial response, and 6 per­cent a partial response.

“Many of these responses were quite durable,” added Dr. Lonial. He added that the majority of responses were in the higher-dose groups.

In addi­tion, 4 per­cent reached a minimal response and 60 per­cent maintained stable disease.

The maximum tolerated dose of MLN9708 was established at 2.0 mg/m2.

Severe to life-threatening treat­ment-related side effects were seen in 64 per­cent of patients, including low platelet counts (55 per­cent), low white blood cell counts (16 per­cent), fatigue (9 per­cent), and rash (7 per­cent).

According to Dr. Lonial, the rate of periph­eral neu­rop­athy was significantly lower among the study participants than what is typically seen in a com­parable patient population treated with Velcade.  Mild periph­eral neu­rop­athy occurred in 11 per­cent of patients.  Dr. Lonial pointed out that these patients already had periph­eral neu­rop­athy at the start of the study.  No cases of severe neu­rop­athy were observed.

“This does represent a major difference between MLN9708 and Velcade,” said Dr. Lonial.

Thirty-eight per­cent of patients required dose reductions due to side effects, and 7 per­cent dis­con­tinued treat­ment due to side effects.

Two patients died during the study, due to progressive disease and an unrelated cardiac disorder.

Dr. Lonial concluded, “This is a very well tolerated oral proteasome inhibitor with infrequent periph­eral neu­rop­athy, and there is a pretty significant suggestion for activity in this heavily pretreated patient population.”

Once Weekly MLN9708 As A Single-Agent Treatment

In this Phase 1 trial, researchers assessed the maximum tolerated dose and efficacy of MLN9708 alone in myeloma patients with re­lapsed or refractory disease. The results of this study were displayed during a poster session at the ASCO meeting.

The study enrolled 52 patients with a median of six prior lines of ther­apy, including Velcade and Revlimid.

Patients received between 0.24 mg/m2 and 3.95 mg/m2 of MLN9708 on days 1, 8, and 15 of a 28-day treat­ment cycle.

Of the 52 patients, 2 per­cent reached a very good partial response, 6 per­cent a partial response, and 2 per­cent a minimal response. An addi­tional 23 per­cent had stable disease.

The maximum tolerated dose was found to be 2.97 mg/m2.

Severe side effects resulting from high dosages, between 2.97 mg/m2 and 3.95 mg/m2, included rash and gastro­in­tes­ti­nal events.

The most common severe side effects included low platelet counts, diarrhea, nausea, low white blood cell counts, and fatigue.

Mild to mod­er­ate cases of periph­eral neu­rop­athy occurred in 12 per­cent of patients.

MLN9708 In Combination With Revlimid And Dexamethasone

In a Phase 1/2 clinical trial, researchers evaluated the safety and efficacy of MLN9708 in com­bi­na­tion with Revlimid and dexamethasone (Decadron) in pre­vi­ously untreated multiple myeloma patients. The results of this study were also displayed during a poster session.

The Phase 1 portion of the study was conducted to determine the safety and maximum tolerated dose of this three-drug regi­men. The goal of the Phase 2 portion was to evaluate the clinical response to this line of treat­ment.

Sixty-five patients who had not pre­vi­ously been treated were enrolled in the study. During Phase 1 of the trial, patients received between 1.68 mg/m2 and 3.95 mg/m2 of MLN9708 on days 1, 8, and 15; 25 mg of Revlimid on days 1 through 21; and 40 mg of dexa­meth­a­sone on days 1, 8, 15, and 22, for a maximum of twelve 28-day treat­ment cycles.

Patients participating in Phase 2 of the trial received a fixed dose of 4.0 mg of MLN9708 on days 1, 8, and 15 along with the same dosages and schedule of Revlimid and dexa­meth­a­sone from Phase 1 of the trial.

Of the 46 evaluable patients, 26 per­cent achieved a complete response, 20 per­cent a very good partial response, and 52 per­cent a partial response, for an over­all response rate of 98 per­cent.

The researchers determined 2.97 mg/m2 of MLN9708 to be the maximum tolerated dose at the end of the Phase 1 study.

Common severe side effects included rash, nausea, and vomiting. Mild to mod­er­ate treat­ment-related periph­eral neu­rop­athy was seen in 22 per­cent of patients.

One patient died during the study after contracting viral pneu­monia.

For more in­­for­ma­tion on the three trials, please see abstract 8017, abstract 8034, and abstract 8033 on the American Society of Clinical Oncology Annual Meeting website.

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