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

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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- Once-Weekly High-Dose Kyprolis Yields Deeper Responses And Longer Remissions Than Twice-Weekly Kyprolis (ASCO & EHA 2018)
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