The initial results from three early-phase clinical trials suggest that the investi­gational drug MLN9708, either alone or in com­bi­na­tion with Revlimid and dexa­methasone, may be an effective treat­ment for both newly diagnosed multiple myeloma patients and patients with re­lapsed and/or treat­ment-resistant disease.

The findings from the three trials were presented earlier this week at the American Society of Hematology (ASH) annual meeting in San Diego.

MLN9708 (ixazomib) belongs to the same class of drugs as Velcade (bor­tez­o­mib), called proteasome inhibitors, and it is being developed by Millennium Pharmaceuticals, the same com­pany that developed Velcade.

However, unlike Velcade, which is given by infusion or injection, MLN9708 can be admin­istered orally in capsule form.

The results for MLN9708 that were presented at ASH are promising.  For example, in the small trial with newly diagnosed myeloma patients, 100 per­cent of the patients had at least a partial response to treat­ment with a com­bi­na­tion of MLN9708, Revlimid, and dexa­meth­a­sone.

In addi­tion, the rate of periph­eral neu­rop­athy among patients treated with MLN9708 appears to be 50 to 75 per­cent lower than seen among patients treated with Velcade.  Peripheral neu­rop­athy is a con­di­tion char­ac­ter­ized by pain and tingling in the extremities.

MLN9708 In Combination With Revlimid And Dexamethasone

Dr. Jesus Berdeja from the Sarah Cannon Research Institute in Nashville, Tennessee, reported interim results from a Phase 1 study of MLN9708 in com­bi­na­tion with Revlimid (lena­lido­mide) and dexamethasone (Decadron) in patients with pre­vi­ously untreated multiple myeloma.

Preclinical studies showed that MLN9708 acted synergistically with Revlimid and dexa­meth­a­sone.

The goal of the Phase 1 study was to determine the safety and maximum tolerated dose of this com­bi­na­tion ther­apy.

Fifteen newly diagnosed patients have been enrolled in the study so far. They received 1.68 mg/m² to 3.95 mg/m² of MLN9708 orally on days 1, 8, and 15 of a 28-day treat­ment cycle. They also received 25 mg of Revlimid on days 1 to 21 of each treat­ment cycle and 40 mg of dexa­meth­a­sone on days 1, 8, 15, and 22 for up to 12 cycles. Transplant-eligible patients could undergo stem cell trans­plan­ta­tion after six cycles.

Thus far in the trial, participants have received a median of five treat­ment cycles. Seventy-three per­cent of patients are still receiving treat­ment.

A full 100 per­cent of the 15 patients enrolled so far in the trial had at least a partial response to the com­bi­na­tion treat­ment after four cycles of treat­ment.

In addi­tion, 33 per­cent of the patients achieved a very good partial response and 27 per­cent achieved a complete response.

Dr. Berdeja pointed out that response to treat­ment was rapid; 93 per­cent of patients experienced at least a 50 per­cent decrease in M-protein, the ab­nor­mal protein produced by myeloma cells, after one treat­ment cycle.

Eighty-seven per­cent of patients experienced drug-related side effects. The most common severe side effects included vomiting (13 per­cent), blood clots (13 per­cent), anemia (13 per­cent), and rash (13 per­cent).

Mild periph­eral neu­rop­athy was observed in 20 per­cent of patients.

Twenty-seven per­cent of patients required Revlimid dose reductions, and 13 per­cent required MLN9708 dose reductions due to side effects.

The maximum tolerated dose for MLN9708 was found to be 2.97 mg/m². However, Dr. Bereja recom­mended a lower dose (2.23 mg/m²) for the Phase 2 trial because the lower dose was as active as the 2.97 mg/m² dose but better tolerated. In addi­tion, he pointed out that the lower dose did not compromise the dosing of the other two agents.

MLN9708 As A Single-Agent Treatment

Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston presented results from a Phase 1/2 clinical trial of single-agent MLN9708 in patients with re­lapsed and treat­ment-resistant multiple myeloma.

A total of 56 patients, with a median age of 65 years, were enrolled in the study. They had received a median of four prior ther­a­pies.

Almost all patients (88 per­cent) had pre­vi­ously received Velcade, 79 per­cent had received Revlimid, 59 per­cent thalidomide (Thalomid), and 4 per­cent carfilzomib.  Fifty-two per­cent of patients dem­onstrated resistance to their last ther­apy, including 28 per­cent who were resistant to Velcade.

The purpose of the study was to determine the maximum tolerated dose of MLN9708.

Patients received 0.24 mg/m² to 2.23 mg/m² of MLN9708 on days 1, 4, 8, and 11 of a 21-day treat­ment cycle.  They received a median of 3.5 treat­ment cycles.

Of the evaluable patients, 13 per­cent had at least a partial response to treat­ment, with 2 per­cent of patients achieving a complete response. Another 61 per­cent of patients have reached stable disease.

Overall, 91 per­cent of patients experienced drug-related side effects including fatigue (46 per­cent of patients), low platelet counts (39 per­cent), nausea (30 per­cent), diarrhea (23 per­cent), vomiting (23 per­cent), rash (21 per­cent), and periph­eral neu­rop­athy (11 per­cent).

Dr. Richardson pointed out that all cases of periph­eral neu­rop­athy were mild to mod­er­ate; none of the patients experienced severe periph­eral neu­rop­athy.

In addi­tion, 32 per­cent of patients required dose reductions due to side effects, and 9 per­cent dis­con­tinued treat­ment due to side effects.

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

Weekly MLN9708 As A Single-Agent Treatment

Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, presented results from another Phase 1 study of MLN9708 in patients with re­lapsed and refractory multiple myeloma.

The objective of this study was to determine the maximum tolerated dose and safety of MLN9708 admin­istered once per week.

The study enrolled 32 patients, who had received a median of six prior ther­a­pies. The median patient age was 64 years old. Seventy-two per­cent of patients had pre­vi­ously received a stem cell trans­plant, and 56 per­cent were resistant to prior ther­apy (including 28 per­cent to Velcade and 41 per­cent to Revlimid or thalido­mide).

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

Overall, patients received a median of two treat­ment cycles. Three patients are cur­rently continuing treat­ment; all others have dis­con­tinued treat­ment, mainly due to disease pro­gres­sion (69 per­cent).

Of the 18 patients who have been evaluated thus far for their response to the drug, one reached a very good partial response and one reached a partial response, for an over­all response rate of 11 per­cent.

Another 8 patients (44 per­cent) achieved stable disease.

The majority of patients (72 per­cent) experienced treat­ment-related side effects. The most common treat­ment-related side effects included fatigue (31 per­cent), low platelet counts (31 per­cent), nausea (28 per­cent), and diarrhea (25 per­cent).

Nine per­cent of patients reported periph­eral neu­rop­athy. Dr. Kumar pointed that all cases of periph­eral neu­rop­athy were mild to mod­er­ate in nature.

Nineteen per­cent of patients required a dose reduction due to side effects, and 11 per­cent dis­con­tinued treat­ment due to side effects.

The maximum tolerated dose for weekly admin­istra­tion has been determined to be 2.97 mg/m².

For more in­­for­ma­tion about these three trials, please see abstract 301, abstract 479, and abstract 816 on the American Society of Hematology annual meeting website.

Also, as a courtesy to The Beacon's readers, Dr. Richardson has made the slides of his presentation available (pdf) for download and viewing.