Pomalidomide Elicits Responses When Other Myeloma Regimens Fail

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.