BCL-2 inhibitor shows potential for treating MM

Staff member giving directions

to an attendee at ASCO 2015

© ASCO/Zach Boyden-Holmes

CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.

In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.

As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.

Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.

“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.

“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”

Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.

Venetoclax in combination

In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.

The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.

The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.

On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.

Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.

The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).

Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.

The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.

Venetoclax as monotherapy

In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.

The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.

After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.

Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.

The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.

The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.

Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%),  fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.

Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.

*Information in the abstract differs from that presented at the meeting.

Staff member giving directions

to an attendee at ASCO 2015

© ASCO/Zach Boyden-Holmes

CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.

In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.

As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.

Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.

“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.

“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”

Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.

Venetoclax in combination

In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.

The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.

The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.

On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.

Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.

The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).

Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.

The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.

Venetoclax as monotherapy

In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.

The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.

After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.

Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.

The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.

The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.

Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%),  fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.

Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.

*Information in the abstract differs from that presented at the meeting.

Staff member giving directions

to an attendee at ASCO 2015

© ASCO/Zach Boyden-Holmes

CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.

In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.

As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.

Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.

“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.

“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”

Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.

Venetoclax in combination

In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.

The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.

The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.

On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m²) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.

Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.

The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).

Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.

The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.

Venetoclax as monotherapy

In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.

The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.

After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.

Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.

The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.

The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.

Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%),  fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).

Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.

Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.

*Information in the abstract differs from that presented at the meeting.