MLN9708 regimen effective with reduced neuropathy risk in multiple myeloma

ATLANTA – Of 65 patients with newly diagnosed multiple myeloma, nearly all had a partial or better response to an all-oral regimen containing the experimental proteasome inhibitor MLN9708.

In the phase I/II study, the overall response rate was 92%. A complete response occurred in 23% on MLN9708 plus lenalidomide (Revlimid) and dexamethasone (Decadron), and 55% had at least a very good partial response.

Patrice Wendling/IMNG Medical Media

Importantly, neuropathy was minimal with the regimen. Grade 1 neuropathy occurred in 13 of the 65 patients (20%); 6 (9%) had grade 2 and 2 (3%) had grade 3 neuropathy, Dr. Shaji K. Kumar said at the annual meeting of the American Society of Hematology.

In contrast, the combination of lenalidomide, bortezomib (Velcade), and dexamethasone produced a partial response or better in 100% of newly diagnosed patients with multiple myeloma in a phase II study, but 80% of them experienced neuropathy, including grade 2 in 27% and grade 3 in 32% (Blood 2010;116:679-86).

“When the MLN9708 was developed, it was clear that it has reduced neurotoxicity compared with what we have seen historically with Velcade, and secondly, it is available orally, so you can just take a pill a day rather than having to go into a physician’s office and get an injection,” Dr. Kumar, professor of medicine at Mayo Clinic in Rochester, Minn., said in an interview.

Based on the promising results, weekly and twice-weekly MLN9708 is being evaluated as a single agent and in combinations for the treatment of relapsed and newly diagnosed multiple myeloma, including as part of a phase III trial of MLN9708 plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone. The trial is currently enrolling adults with relapsed and/or refractory disease (NCT01564537). “MLN9708 is perfectly placed to be able to be combined in regimens that are highly efficacious, but at the same time are better tolerated,” he added.

In the current study, 65 patients received MLN9708 on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 for up to 12 cycles of 28 days, and were maintained on MLN9708 on days 1, 8, and 15 until disease progression or toxicity. The maximum tolerated dose of MLN9708 was identified in 15 patients in phase I as 2.97 mg/m2. A fixed dose of 4 mg weekly, equivalent to 2.23 mg/m2, was given to another 50 patients in phase II.

Patients also received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. Patients received a median of 6 cycles of MLN9708 in phase I (range, 1-19) and 7 (range, 1-19) in phase II. Their median age was 66 years, and 25% had unfavorable cytogenetics. The median time to first response was one cycle, and the median duration of response was not reached. Responses increased with the number of cycles and deepened over time, Dr. Kumar said.

Complete responses were reported in 19% of 47 patients receiving 4 cycles, very good partial responses in 30%, and partial responses in 45% (overall response rate, 94%), improving after 8 cycles in 19 patients to response rates of 32%, 26%, and 37%, respectively (overall response rate, 95%). Of three evaluable patients who completed 12 cycles, two achieved a complete response and one had a very good partial response.

“So we are fairly confident we will see an increase in response over time,” he said, noting that similar responses were seen in patients with favorable and unfavorable cytogenetics. At the time of the analysis, 27 of the 65 patients remained on treatment, 20 had proceeded to stem cell transplantation, 3 patients progressed, and 1 patient died after cycle 4, possibly related to treatment or alternatively to their underlying disease state, Dr. Kumar said.

The estimated 1-year progression-free survival probability was 93%. Seven additional patients discontinued therapy because of adverse events, including four due to treatment-related AEs. Serious AEs were seen in about 20% of patients, with grade 3 neutropenia and rash being the most common. The most common side effects of any grade were rash (68%), fatigue (48%), nausea (42%), vomiting (32%), and diarrhea (38%). Side effects were manageable with dose modifications and supportive care, Dr. Kumar said.

MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization, with a median of 11.3 x 106/L CD34-positive cells harvested (range, 5-28 x 106/L). Dr. Kumar reported research funding from study sponsor Millennium Pharmaceuticals. His coauthors reported commercial relationships including employment with Millennium.

[email protected]

ATLANTA – Of 65 patients with newly diagnosed multiple myeloma, nearly all had a partial or better response to an all-oral regimen containing the experimental proteasome inhibitor MLN9708.

In the phase I/II study, the overall response rate was 92%. A complete response occurred in 23% on MLN9708 plus lenalidomide (Revlimid) and dexamethasone (Decadron), and 55% had at least a very good partial response.

Patrice Wendling/IMNG Medical Media

Importantly, neuropathy was minimal with the regimen. Grade 1 neuropathy occurred in 13 of the 65 patients (20%); 6 (9%) had grade 2 and 2 (3%) had grade 3 neuropathy, Dr. Shaji K. Kumar said at the annual meeting of the American Society of Hematology.

In contrast, the combination of lenalidomide, bortezomib (Velcade), and dexamethasone produced a partial response or better in 100% of newly diagnosed patients with multiple myeloma in a phase II study, but 80% of them experienced neuropathy, including grade 2 in 27% and grade 3 in 32% (Blood 2010;116:679-86).

“When the MLN9708 was developed, it was clear that it has reduced neurotoxicity compared with what we have seen historically with Velcade, and secondly, it is available orally, so you can just take a pill a day rather than having to go into a physician’s office and get an injection,” Dr. Kumar, professor of medicine at Mayo Clinic in Rochester, Minn., said in an interview.

Based on the promising results, weekly and twice-weekly MLN9708 is being evaluated as a single agent and in combinations for the treatment of relapsed and newly diagnosed multiple myeloma, including as part of a phase III trial of MLN9708 plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone. The trial is currently enrolling adults with relapsed and/or refractory disease (NCT01564537). “MLN9708 is perfectly placed to be able to be combined in regimens that are highly efficacious, but at the same time are better tolerated,” he added.

In the current study, 65 patients received MLN9708 on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 for up to 12 cycles of 28 days, and were maintained on MLN9708 on days 1, 8, and 15 until disease progression or toxicity. The maximum tolerated dose of MLN9708 was identified in 15 patients in phase I as 2.97 mg/m2. A fixed dose of 4 mg weekly, equivalent to 2.23 mg/m2, was given to another 50 patients in phase II.

Patients also received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. Patients received a median of 6 cycles of MLN9708 in phase I (range, 1-19) and 7 (range, 1-19) in phase II. Their median age was 66 years, and 25% had unfavorable cytogenetics. The median time to first response was one cycle, and the median duration of response was not reached. Responses increased with the number of cycles and deepened over time, Dr. Kumar said.

Complete responses were reported in 19% of 47 patients receiving 4 cycles, very good partial responses in 30%, and partial responses in 45% (overall response rate, 94%), improving after 8 cycles in 19 patients to response rates of 32%, 26%, and 37%, respectively (overall response rate, 95%). Of three evaluable patients who completed 12 cycles, two achieved a complete response and one had a very good partial response.

“So we are fairly confident we will see an increase in response over time,” he said, noting that similar responses were seen in patients with favorable and unfavorable cytogenetics. At the time of the analysis, 27 of the 65 patients remained on treatment, 20 had proceeded to stem cell transplantation, 3 patients progressed, and 1 patient died after cycle 4, possibly related to treatment or alternatively to their underlying disease state, Dr. Kumar said.

The estimated 1-year progression-free survival probability was 93%. Seven additional patients discontinued therapy because of adverse events, including four due to treatment-related AEs. Serious AEs were seen in about 20% of patients, with grade 3 neutropenia and rash being the most common. The most common side effects of any grade were rash (68%), fatigue (48%), nausea (42%), vomiting (32%), and diarrhea (38%). Side effects were manageable with dose modifications and supportive care, Dr. Kumar said.

MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization, with a median of 11.3 x 106/L CD34-positive cells harvested (range, 5-28 x 106/L). Dr. Kumar reported research funding from study sponsor Millennium Pharmaceuticals. His coauthors reported commercial relationships including employment with Millennium.

[email protected]

ATLANTA – Of 65 patients with newly diagnosed multiple myeloma, nearly all had a partial or better response to an all-oral regimen containing the experimental proteasome inhibitor MLN9708.

In the phase I/II study, the overall response rate was 92%. A complete response occurred in 23% on MLN9708 plus lenalidomide (Revlimid) and dexamethasone (Decadron), and 55% had at least a very good partial response.

Patrice Wendling/IMNG Medical Media

Importantly, neuropathy was minimal with the regimen. Grade 1 neuropathy occurred in 13 of the 65 patients (20%); 6 (9%) had grade 2 and 2 (3%) had grade 3 neuropathy, Dr. Shaji K. Kumar said at the annual meeting of the American Society of Hematology.

In contrast, the combination of lenalidomide, bortezomib (Velcade), and dexamethasone produced a partial response or better in 100% of newly diagnosed patients with multiple myeloma in a phase II study, but 80% of them experienced neuropathy, including grade 2 in 27% and grade 3 in 32% (Blood 2010;116:679-86).

“When the MLN9708 was developed, it was clear that it has reduced neurotoxicity compared with what we have seen historically with Velcade, and secondly, it is available orally, so you can just take a pill a day rather than having to go into a physician’s office and get an injection,” Dr. Kumar, professor of medicine at Mayo Clinic in Rochester, Minn., said in an interview.

Based on the promising results, weekly and twice-weekly MLN9708 is being evaluated as a single agent and in combinations for the treatment of relapsed and newly diagnosed multiple myeloma, including as part of a phase III trial of MLN9708 plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone. The trial is currently enrolling adults with relapsed and/or refractory disease (NCT01564537). “MLN9708 is perfectly placed to be able to be combined in regimens that are highly efficacious, but at the same time are better tolerated,” he added.

In the current study, 65 patients received MLN9708 on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 for up to 12 cycles of 28 days, and were maintained on MLN9708 on days 1, 8, and 15 until disease progression or toxicity. The maximum tolerated dose of MLN9708 was identified in 15 patients in phase I as 2.97 mg/m2. A fixed dose of 4 mg weekly, equivalent to 2.23 mg/m2, was given to another 50 patients in phase II.

Patients also received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. Patients received a median of 6 cycles of MLN9708 in phase I (range, 1-19) and 7 (range, 1-19) in phase II. Their median age was 66 years, and 25% had unfavorable cytogenetics. The median time to first response was one cycle, and the median duration of response was not reached. Responses increased with the number of cycles and deepened over time, Dr. Kumar said.

Complete responses were reported in 19% of 47 patients receiving 4 cycles, very good partial responses in 30%, and partial responses in 45% (overall response rate, 94%), improving after 8 cycles in 19 patients to response rates of 32%, 26%, and 37%, respectively (overall response rate, 95%). Of three evaluable patients who completed 12 cycles, two achieved a complete response and one had a very good partial response.

“So we are fairly confident we will see an increase in response over time,” he said, noting that similar responses were seen in patients with favorable and unfavorable cytogenetics. At the time of the analysis, 27 of the 65 patients remained on treatment, 20 had proceeded to stem cell transplantation, 3 patients progressed, and 1 patient died after cycle 4, possibly related to treatment or alternatively to their underlying disease state, Dr. Kumar said.

The estimated 1-year progression-free survival probability was 93%. Seven additional patients discontinued therapy because of adverse events, including four due to treatment-related AEs. Serious AEs were seen in about 20% of patients, with grade 3 neutropenia and rash being the most common. The most common side effects of any grade were rash (68%), fatigue (48%), nausea (42%), vomiting (32%), and diarrhea (38%). Side effects were manageable with dose modifications and supportive care, Dr. Kumar said.

MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization, with a median of 11.3 x 106/L CD34-positive cells harvested (range, 5-28 x 106/L). Dr. Kumar reported research funding from study sponsor Millennium Pharmaceuticals. His coauthors reported commercial relationships including employment with Millennium.

[email protected]