Lymphoma & Plasma Cell Disorders

The Food and Drug Administration has approved a subcutaneous formulation of bortezomib, which will join the intravenous formulation as treatment for multiple myeloma and mantle cell lymphoma after at least one prior therapy, according to its manufacturer, Millennium: The Takeda Oncology Co.

Bortezomib is a proteasome inhibitor marketed as Velcade; the intravenous formulation was approved in 2003.

Approval of the subcutaneous formulation was based on a randomized, phase III open label noninferiority international study of patients with relapsed multiple myeloma, who had not received bortezomib previously. The study compared the overall response rate (ORR) after four treatment cycles in those treated with the subcutaneous formulation (145) and those treated with the IV formulation (73 patients); noninferiority was defined as retaining 60% of the IV treatment effect. After four cycles, the ORR was 43% among those on the subcutaneous formulation and 42% among those on the IV formulation. These results were published in May (Lancet Oncol. 2011;12:431-40).

Overall, the safety profile for the two arms was similar except for some serious adverse events, including peripheral neuropathy (PN): The rate of PN that was grade 3 or greater was 6% among those on the subcutaneous formulation, compared with 16% among those on the IV formulation, a significant difference. The rate of PN of any grade was also lower among those on the subcutaneous formulation (38% vs. 53%).

Other adverse events that were grade 3 and greater that were at least 5% higher among those on the IV formulation on were thrombocytopenia (6% vs. 16%), thrombocytopenia (13% vs. 19%), and neuralgia (3% vs. 9%).

A contraindication against intrathecal administration of bortezomib has been added to the label, because of fatal events that have resulted from inadvertent intrathecal administration of the drug.

The study was funded by Johnson & Johnson Pharmaceutical Research and Development and Millennium Pharmaceuticals.

The Food and Drug Administration has approved a subcutaneous formulation of bortezomib, which will join the intravenous formulation as treatment for multiple myeloma and mantle cell lymphoma after at least one prior therapy, according to its manufacturer, Millennium: The Takeda Oncology Co.

Bortezomib is a proteasome inhibitor marketed as Velcade; the intravenous formulation was approved in 2003.

Approval of the subcutaneous formulation was based on a randomized, phase III open label noninferiority international study of patients with relapsed multiple myeloma, who had not received bortezomib previously. The study compared the overall response rate (ORR) after four treatment cycles in those treated with the subcutaneous formulation (145) and those treated with the IV formulation (73 patients); noninferiority was defined as retaining 60% of the IV treatment effect. After four cycles, the ORR was 43% among those on the subcutaneous formulation and 42% among those on the IV formulation. These results were published in May (Lancet Oncol. 2011;12:431-40).

Overall, the safety profile for the two arms was similar except for some serious adverse events, including peripheral neuropathy (PN): The rate of PN that was grade 3 or greater was 6% among those on the subcutaneous formulation, compared with 16% among those on the IV formulation, a significant difference. The rate of PN of any grade was also lower among those on the subcutaneous formulation (38% vs. 53%).

Other adverse events that were grade 3 and greater that were at least 5% higher among those on the IV formulation on were thrombocytopenia (6% vs. 16%), thrombocytopenia (13% vs. 19%), and neuralgia (3% vs. 9%).

A contraindication against intrathecal administration of bortezomib has been added to the label, because of fatal events that have resulted from inadvertent intrathecal administration of the drug.

The study was funded by Johnson & Johnson Pharmaceutical Research and Development and Millennium Pharmaceuticals.

The Food and Drug Administration has approved a subcutaneous formulation of bortezomib, which will join the intravenous formulation as treatment for multiple myeloma and mantle cell lymphoma after at least one prior therapy, according to its manufacturer, Millennium: The Takeda Oncology Co.

Bortezomib is a proteasome inhibitor marketed as Velcade; the intravenous formulation was approved in 2003.

Approval of the subcutaneous formulation was based on a randomized, phase III open label noninferiority international study of patients with relapsed multiple myeloma, who had not received bortezomib previously. The study compared the overall response rate (ORR) after four treatment cycles in those treated with the subcutaneous formulation (145) and those treated with the IV formulation (73 patients); noninferiority was defined as retaining 60% of the IV treatment effect. After four cycles, the ORR was 43% among those on the subcutaneous formulation and 42% among those on the IV formulation. These results were published in May (Lancet Oncol. 2011;12:431-40).

Overall, the safety profile for the two arms was similar except for some serious adverse events, including peripheral neuropathy (PN): The rate of PN that was grade 3 or greater was 6% among those on the subcutaneous formulation, compared with 16% among those on the IV formulation, a significant difference. The rate of PN of any grade was also lower among those on the subcutaneous formulation (38% vs. 53%).

Other adverse events that were grade 3 and greater that were at least 5% higher among those on the IV formulation on were thrombocytopenia (6% vs. 16%), thrombocytopenia (13% vs. 19%), and neuralgia (3% vs. 9%).

A contraindication against intrathecal administration of bortezomib has been added to the label, because of fatal events that have resulted from inadvertent intrathecal administration of the drug.

The study was funded by Johnson & Johnson Pharmaceutical Research and Development and Millennium Pharmaceuticals.

SAN DIEGO – A provocative analysis suggests that a sequence of bortezomib and lenalidomide provides a better survival advantage than regimens with three or more agents in patients with multiple myeloma and high-risk cytogenetics.*

"While the limitations of this retrospective study limit drawing definitive conclusions, it appears that poor cytogenetics and biology trump treatment intensification," Dr. Rachid Baz and his colleagues stated in a poster presentation at the annual meeting of the American Society of Hematology.

The investigators reported on 208 patients with multiple myeloma who received bortezomib (Velcade) and lenalidomide (Revlimid), nonconcurrently between January 2004 and August 2010 at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. The patients were stratified by treatment into six groups: lenalidomide with or without dexamethasone (lenalidomide A) or lenalidomide in combination with two or more agents (lenalidomide B); bortezomib with or with dexamethasone (bortezomib A) or bortezomib in combination with two or more agents (bortezomib B); and finally, only doublets or single agents (nonintensive therapy) or three or more agents in combination (intensive therapy).

No differences were observed between the lenalidomide A and B, bortezomib A and B, or intensive and nonintensive therapy groups in the baseline characteristics of age, International Staging System (ISS) and Durie/Salmon stage, beta2microglobulin or renal function, presence of poor-risk cytogenetics, and frequency of high-dose therapy.

Poor-risk cytogenetics, an increasingly fluid term in the context of growing success with novel myeloma agents, included deletions 13q and 17p, translocations, (4;14) and (14;16) or hypodiploidy.

Lenalidomide A patients had a trend toward improved median overall survival at 72 months, compared with 57 months for the lenalidomide B group receiving more complex regimens (P = .07), reported Dr. Baz, with Moffitt’s hematologic malignancies and experimental therapeutics departments.

Median overall survival, the study’s primary end point, however, was significantly improved in the bortezomib A group at 72 months vs. 45 months in the bortezomib B group (P = .02).

Similarly, the nonintensive therapy group lived significantly longer for 74 months vs. 57 months for the intensive therapy group (P = .03).

Notably, patients with high-risk cytogenetics had significantly worse survival if they received intensive therapy rather than nonintensive therapy (median 44 months vs. 72 months; P = .01), he noted. In contrast, patients without high-risk cytogenetics had similar overall survival regardless of whether they belonged to the intensive therapy or nonintensive therapy groups (median 76 months vs. 75 months).

On multivariate analysis that adjusted for known covariates linked to myeloma survival such as ISS stage and high-dose therapy, the only features predictive of poor outcome were renal failure at baseline and intensive therapy.

Dr. Baz said the investigators were surprised by the counterintuitive results and that they could be due to bias from an unidentified confounding factor. For example, it’s possible that high-risk patients who appeared more ill were more likely to be given more intensive therapy by the practicing physician and may have had poor outcomes nonetheless, whereas high-risk patients who appeared more stable were more likely to be given less intensive therapy, but did well because of more indolent disease characteristics.

A potential biologic explanation for the finding might be related to genomic instabilities more commonly seen in high-risk myeloma.

"Patients with high-risk disease have myeloma cells that are more likely to acquire drug resistance faster," he said in an interview. "As a result, if you expose those myeloma cells to many drugs at once, they may acquire resistance to them faster and you get less mileage than if you spread out the drugs."

Dr. Baz said further study at the molecular level is needed to see how drug resistance develops in myeloma in the context of combination therapy with three or four drugs versus treatment with one or two drugs.

"I think the finding is hypothesis generating," he said. "It doesn’t change my practice with the patients I see today, but it needs more study."

Baseline characteristics of the non-intensive and intensive therapy groups were: age (58.9 years, 58.5 years), heavy chain IgG (60%, 63%), light chain Kappa (58%, 67%), ISS stage II (40%, 38%), ISS III (24%, 33%), Durie/Salmon stage III (75%, 85%), creatinine at least 2.0 mg/dL (12%, 13%), presence of bone disease (67%, 80%), poor-risk cytogenetics (43%, 36%), prior high-dose therapy (64%, 66%), and thalidomide use (59%, 47%).

The only significant difference between two groups was the presence of more males in the intensive group (73% vs. 52%; P = .01).

Dr. Baz reported research funding from Celgene and membership on an entity’s board of directors or advisory committee and research funding from Millennium Pharmaceuticals. His coauthors reported similar relationships with Celgene, Millennium, Novartis, and Allergan. 

*CLARIFICATION 1/23/12 The status of bortezomib and lenalidomide in treatment for multiple myeloma was clarified in this sentence.

SAN DIEGO – A provocative analysis suggests that a sequence of bortezomib and lenalidomide provides a better survival advantage than regimens with three or more agents in patients with multiple myeloma and high-risk cytogenetics.*

"While the limitations of this retrospective study limit drawing definitive conclusions, it appears that poor cytogenetics and biology trump treatment intensification," Dr. Rachid Baz and his colleagues stated in a poster presentation at the annual meeting of the American Society of Hematology.

The investigators reported on 208 patients with multiple myeloma who received bortezomib (Velcade) and lenalidomide (Revlimid), nonconcurrently between January 2004 and August 2010 at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. The patients were stratified by treatment into six groups: lenalidomide with or without dexamethasone (lenalidomide A) or lenalidomide in combination with two or more agents (lenalidomide B); bortezomib with or with dexamethasone (bortezomib A) or bortezomib in combination with two or more agents (bortezomib B); and finally, only doublets or single agents (nonintensive therapy) or three or more agents in combination (intensive therapy).

No differences were observed between the lenalidomide A and B, bortezomib A and B, or intensive and nonintensive therapy groups in the baseline characteristics of age, International Staging System (ISS) and Durie/Salmon stage, beta2microglobulin or renal function, presence of poor-risk cytogenetics, and frequency of high-dose therapy.

Poor-risk cytogenetics, an increasingly fluid term in the context of growing success with novel myeloma agents, included deletions 13q and 17p, translocations, (4;14) and (14;16) or hypodiploidy.

Lenalidomide A patients had a trend toward improved median overall survival at 72 months, compared with 57 months for the lenalidomide B group receiving more complex regimens (P = .07), reported Dr. Baz, with Moffitt’s hematologic malignancies and experimental therapeutics departments.

Median overall survival, the study’s primary end point, however, was significantly improved in the bortezomib A group at 72 months vs. 45 months in the bortezomib B group (P = .02).

Similarly, the nonintensive therapy group lived significantly longer for 74 months vs. 57 months for the intensive therapy group (P = .03).

Notably, patients with high-risk cytogenetics had significantly worse survival if they received intensive therapy rather than nonintensive therapy (median 44 months vs. 72 months; P = .01), he noted. In contrast, patients without high-risk cytogenetics had similar overall survival regardless of whether they belonged to the intensive therapy or nonintensive therapy groups (median 76 months vs. 75 months).

On multivariate analysis that adjusted for known covariates linked to myeloma survival such as ISS stage and high-dose therapy, the only features predictive of poor outcome were renal failure at baseline and intensive therapy.

Dr. Baz said the investigators were surprised by the counterintuitive results and that they could be due to bias from an unidentified confounding factor. For example, it’s possible that high-risk patients who appeared more ill were more likely to be given more intensive therapy by the practicing physician and may have had poor outcomes nonetheless, whereas high-risk patients who appeared more stable were more likely to be given less intensive therapy, but did well because of more indolent disease characteristics.

A potential biologic explanation for the finding might be related to genomic instabilities more commonly seen in high-risk myeloma.

"Patients with high-risk disease have myeloma cells that are more likely to acquire drug resistance faster," he said in an interview. "As a result, if you expose those myeloma cells to many drugs at once, they may acquire resistance to them faster and you get less mileage than if you spread out the drugs."

Dr. Baz said further study at the molecular level is needed to see how drug resistance develops in myeloma in the context of combination therapy with three or four drugs versus treatment with one or two drugs.

"I think the finding is hypothesis generating," he said. "It doesn’t change my practice with the patients I see today, but it needs more study."

Baseline characteristics of the non-intensive and intensive therapy groups were: age (58.9 years, 58.5 years), heavy chain IgG (60%, 63%), light chain Kappa (58%, 67%), ISS stage II (40%, 38%), ISS III (24%, 33%), Durie/Salmon stage III (75%, 85%), creatinine at least 2.0 mg/dL (12%, 13%), presence of bone disease (67%, 80%), poor-risk cytogenetics (43%, 36%), prior high-dose therapy (64%, 66%), and thalidomide use (59%, 47%).

The only significant difference between two groups was the presence of more males in the intensive group (73% vs. 52%; P = .01).

Dr. Baz reported research funding from Celgene and membership on an entity’s board of directors or advisory committee and research funding from Millennium Pharmaceuticals. His coauthors reported similar relationships with Celgene, Millennium, Novartis, and Allergan. 

*CLARIFICATION 1/23/12 The status of bortezomib and lenalidomide in treatment for multiple myeloma was clarified in this sentence.

SAN DIEGO – A provocative analysis suggests that a sequence of bortezomib and lenalidomide provides a better survival advantage than regimens with three or more agents in patients with multiple myeloma and high-risk cytogenetics.*

"While the limitations of this retrospective study limit drawing definitive conclusions, it appears that poor cytogenetics and biology trump treatment intensification," Dr. Rachid Baz and his colleagues stated in a poster presentation at the annual meeting of the American Society of Hematology.

The investigators reported on 208 patients with multiple myeloma who received bortezomib (Velcade) and lenalidomide (Revlimid), nonconcurrently between January 2004 and August 2010 at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. The patients were stratified by treatment into six groups: lenalidomide with or without dexamethasone (lenalidomide A) or lenalidomide in combination with two or more agents (lenalidomide B); bortezomib with or with dexamethasone (bortezomib A) or bortezomib in combination with two or more agents (bortezomib B); and finally, only doublets or single agents (nonintensive therapy) or three or more agents in combination (intensive therapy).

No differences were observed between the lenalidomide A and B, bortezomib A and B, or intensive and nonintensive therapy groups in the baseline characteristics of age, International Staging System (ISS) and Durie/Salmon stage, beta2microglobulin or renal function, presence of poor-risk cytogenetics, and frequency of high-dose therapy.

Poor-risk cytogenetics, an increasingly fluid term in the context of growing success with novel myeloma agents, included deletions 13q and 17p, translocations, (4;14) and (14;16) or hypodiploidy.

Lenalidomide A patients had a trend toward improved median overall survival at 72 months, compared with 57 months for the lenalidomide B group receiving more complex regimens (P = .07), reported Dr. Baz, with Moffitt’s hematologic malignancies and experimental therapeutics departments.

Median overall survival, the study’s primary end point, however, was significantly improved in the bortezomib A group at 72 months vs. 45 months in the bortezomib B group (P = .02).

Similarly, the nonintensive therapy group lived significantly longer for 74 months vs. 57 months for the intensive therapy group (P = .03).

Notably, patients with high-risk cytogenetics had significantly worse survival if they received intensive therapy rather than nonintensive therapy (median 44 months vs. 72 months; P = .01), he noted. In contrast, patients without high-risk cytogenetics had similar overall survival regardless of whether they belonged to the intensive therapy or nonintensive therapy groups (median 76 months vs. 75 months).

On multivariate analysis that adjusted for known covariates linked to myeloma survival such as ISS stage and high-dose therapy, the only features predictive of poor outcome were renal failure at baseline and intensive therapy.

Dr. Baz said the investigators were surprised by the counterintuitive results and that they could be due to bias from an unidentified confounding factor. For example, it’s possible that high-risk patients who appeared more ill were more likely to be given more intensive therapy by the practicing physician and may have had poor outcomes nonetheless, whereas high-risk patients who appeared more stable were more likely to be given less intensive therapy, but did well because of more indolent disease characteristics.

A potential biologic explanation for the finding might be related to genomic instabilities more commonly seen in high-risk myeloma.

"Patients with high-risk disease have myeloma cells that are more likely to acquire drug resistance faster," he said in an interview. "As a result, if you expose those myeloma cells to many drugs at once, they may acquire resistance to them faster and you get less mileage than if you spread out the drugs."

Dr. Baz said further study at the molecular level is needed to see how drug resistance develops in myeloma in the context of combination therapy with three or four drugs versus treatment with one or two drugs.

"I think the finding is hypothesis generating," he said. "It doesn’t change my practice with the patients I see today, but it needs more study."

Baseline characteristics of the non-intensive and intensive therapy groups were: age (58.9 years, 58.5 years), heavy chain IgG (60%, 63%), light chain Kappa (58%, 67%), ISS stage II (40%, 38%), ISS III (24%, 33%), Durie/Salmon stage III (75%, 85%), creatinine at least 2.0 mg/dL (12%, 13%), presence of bone disease (67%, 80%), poor-risk cytogenetics (43%, 36%), prior high-dose therapy (64%, 66%), and thalidomide use (59%, 47%).

The only significant difference between two groups was the presence of more males in the intensive group (73% vs. 52%; P = .01).

Dr. Baz reported research funding from Celgene and membership on an entity’s board of directors or advisory committee and research funding from Millennium Pharmaceuticals. His coauthors reported similar relationships with Celgene, Millennium, Novartis, and Allergan. 

*CLARIFICATION 1/23/12 The status of bortezomib and lenalidomide in treatment for multiple myeloma was clarified in this sentence.

SAN DIEGO – Adding the investigational protease inhibitor carfilzomib to lenalidomide and low-dose dexamethasone produced responses comparable with those achieved with the best frontline regimens in multiple myeloma, final results from a multicenter phase I/II study indicate.

Nearly all, 94%, of 49 evaluable patients with newly diagnosed multiple myeloma achieved at least a partial response with the triple combination, and 53% attained a near complete, complete, or stringent complete response (nCR/CR/sCR).

Responses also continued to improve with time, with 79% of patients reaching a nCR/CR/sCR after 12 cycles, Dr. Andrzej J. Jakubowiak reported at the annual meeting of the American Society of Hematology on behalf of the Multiple Myeloma Research Consortium. Although the data are still being evaluated, about half of the nCR/CR/sCRs were complete responses.

"These response rates appear to compare favorably to the best frontline regimens in myeloma and, I would dare to say, they compare favorably to treatment sequences with transplant," said Dr. Jakubowiak, director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone previously posted an encouraging overall response rate of 78% and a nCR/CR rate of 40% with a low toxicity profile in the relapsed and/or refractory setting, providing the rationale for two ongoing phase III trials. The ASPIRE trial is evaluating lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma; the FOCUS trial, to support registration in Europe, is evaluating single-agent carfilzomib in relapsed/refractory myeloma.

Onyx Pharmaceuticals has announced that the U.S. Food and Drug Administration is giving carfilzomib a standard review in the treatment of relapsed and refractory myeloma, with a decision expected by July 27.

An expanded access program is also underway in partnership with the Multiple Myeloma Research Foundation for eligible patients in the United States with relapsed and refractory myeloma for whom no satisfactory treatment alternatives are available.

The carfilzomib, lenalidomide, and dexamethasone (CRd) regimen was one of several (including such novel therapies as oral MLN9708 protease inhibitor and the so-called BiRD regimen of clarithromycin [Biaxin] with lenalidomide and dexamethasone) for which impressive results were reported at the ASH meeting. "All of these drugs will find their own place" Dr. Jakubowiak said, but, he added, CRd is "the strongest regimen I’ve used, and I’ve used a variety of these regimens."

He noted that his patients continue to come to the clinic with no complaints of toxicity and that their responses continue to improve, providing further stimulus for those trying to sort through the abundance of novel myeloma therapies.

The current study included 53 patients who were eligible or ineligible for transplant: they received eight cycles of induction therapy with IV carfilzomib 20, 27, or 36 mg/m²; oral lenalidomide 25 mg, and oral dexamethasone at 40 mg for cycles 1-4 and at 20 mg for cycles 5-8, followed by maintenance therapy at the doses tolerated at the end of the eight cycles until disease progression or toxicity. Patients with at least a partial response after four cycles could proceed to stem cell transplant.

Their median age was 59 years, and 60% had advanced myeloma and 33% had unfavorable cytogenetics including deletion 17p.

After a median of 9.5 months follow-up, only one patient progressed and all patients were alive. Of these, 88% of patients remained on treatment, and 24 of 27 patients who began maintenance therapy continued on CRd maintenance, said Dr. Jakubowiak.

Dose modifications were required in 16 patients, and one patient discontinued therapy because of toxicity. Peripheral neuropathy was reported in almost one-quarter of patients, but all cases were grade 1/2. Dyspnea was reported in about one-third of patients, but it was quickly resolving, he noted.

Responses in the 16 patients with unfavorable cytogenetics were similar to all other patients, and included at least a partial response in 100% and nCR/CR/sCR in 56%, Dr. Jakubowiak said.

Dr. Ravi Vij of Washington University, St. Louis, presented final results of single-agent carfilzomib in bortezomib (Velcade)-naive patients in the separate phase II PX-171-004 study in myeloma that had relapsed after one to three lines of therapy.

The trial enrolled 165 patients, with one cohort receiving IV carfilzomib 20 mg/m² for all 12 cycles and the second cohort given carfilzomib 20 mg/m² for cycle 1 with escalation to 27 mg/m² in all subsequent cycles.

A total of 129 patients were bortezomib-naive, including 59 in cohort 1 and 70 in cohort 2. At baseline, 15% had unfavorable cytogenetics, 52% had neuropathy, and two-thirds were refractory to their most recent therapy.

The overall response rate was 42% in cohort 1 and 52% in cohort 2, Dr. Vij reported. The median time to disease progression was 8.3 months and median duration of response was 13.1 months in cohort 1. Neither end point had been reached in cohort 2.

Dr. Vij noted that the higher response rates in cohort 2 do not appear to be associated with higher side effects. Mild to moderate peripheral neuropathy was reported in 14% of cohort 1 and 19% of cohort 2. Only one case of grade-3 peripheral neuropathy was reported in cohort 1 and none in cohort 2.

The most common adverse events in cohort 1 and cohort 2, respectively, were fatigue (71%, 54%), nausea (54%, 44%), anemia (46%, 39%), dyspnea (49%, 30%), cough (39%, 30%) and pyrexia (36%, 33%). The majority were grade 1/2; adverse events leading to carfilzomib discontinuation occurred in 22% of cohort 1 and 10% of cohort 2, he said.

These data are suggestive of a dose-response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007, Dr. Vij said.

The trials were sponsored by Onyx Pharmaceuticals. Dr. Jakubowiak and his coauthors and Dr. Vij and his coauthors reported financial relationships with several pharmaceutical firms, including Onyx.

SAN DIEGO – Adding the investigational protease inhibitor carfilzomib to lenalidomide and low-dose dexamethasone produced responses comparable with those achieved with the best frontline regimens in multiple myeloma, final results from a multicenter phase I/II study indicate.

Nearly all, 94%, of 49 evaluable patients with newly diagnosed multiple myeloma achieved at least a partial response with the triple combination, and 53% attained a near complete, complete, or stringent complete response (nCR/CR/sCR).

Responses also continued to improve with time, with 79% of patients reaching a nCR/CR/sCR after 12 cycles, Dr. Andrzej J. Jakubowiak reported at the annual meeting of the American Society of Hematology on behalf of the Multiple Myeloma Research Consortium. Although the data are still being evaluated, about half of the nCR/CR/sCRs were complete responses.

"These response rates appear to compare favorably to the best frontline regimens in myeloma and, I would dare to say, they compare favorably to treatment sequences with transplant," said Dr. Jakubowiak, director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone previously posted an encouraging overall response rate of 78% and a nCR/CR rate of 40% with a low toxicity profile in the relapsed and/or refractory setting, providing the rationale for two ongoing phase III trials. The ASPIRE trial is evaluating lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma; the FOCUS trial, to support registration in Europe, is evaluating single-agent carfilzomib in relapsed/refractory myeloma.

Onyx Pharmaceuticals has announced that the U.S. Food and Drug Administration is giving carfilzomib a standard review in the treatment of relapsed and refractory myeloma, with a decision expected by July 27.

An expanded access program is also underway in partnership with the Multiple Myeloma Research Foundation for eligible patients in the United States with relapsed and refractory myeloma for whom no satisfactory treatment alternatives are available.

The carfilzomib, lenalidomide, and dexamethasone (CRd) regimen was one of several (including such novel therapies as oral MLN9708 protease inhibitor and the so-called BiRD regimen of clarithromycin [Biaxin] with lenalidomide and dexamethasone) for which impressive results were reported at the ASH meeting. "All of these drugs will find their own place" Dr. Jakubowiak said, but, he added, CRd is "the strongest regimen I’ve used, and I’ve used a variety of these regimens."

He noted that his patients continue to come to the clinic with no complaints of toxicity and that their responses continue to improve, providing further stimulus for those trying to sort through the abundance of novel myeloma therapies.

The current study included 53 patients who were eligible or ineligible for transplant: they received eight cycles of induction therapy with IV carfilzomib 20, 27, or 36 mg/m²; oral lenalidomide 25 mg, and oral dexamethasone at 40 mg for cycles 1-4 and at 20 mg for cycles 5-8, followed by maintenance therapy at the doses tolerated at the end of the eight cycles until disease progression or toxicity. Patients with at least a partial response after four cycles could proceed to stem cell transplant.

Their median age was 59 years, and 60% had advanced myeloma and 33% had unfavorable cytogenetics including deletion 17p.

After a median of 9.5 months follow-up, only one patient progressed and all patients were alive. Of these, 88% of patients remained on treatment, and 24 of 27 patients who began maintenance therapy continued on CRd maintenance, said Dr. Jakubowiak.

Dose modifications were required in 16 patients, and one patient discontinued therapy because of toxicity. Peripheral neuropathy was reported in almost one-quarter of patients, but all cases were grade 1/2. Dyspnea was reported in about one-third of patients, but it was quickly resolving, he noted.

Responses in the 16 patients with unfavorable cytogenetics were similar to all other patients, and included at least a partial response in 100% and nCR/CR/sCR in 56%, Dr. Jakubowiak said.

Dr. Ravi Vij of Washington University, St. Louis, presented final results of single-agent carfilzomib in bortezomib (Velcade)-naive patients in the separate phase II PX-171-004 study in myeloma that had relapsed after one to three lines of therapy.

The trial enrolled 165 patients, with one cohort receiving IV carfilzomib 20 mg/m² for all 12 cycles and the second cohort given carfilzomib 20 mg/m² for cycle 1 with escalation to 27 mg/m² in all subsequent cycles.

A total of 129 patients were bortezomib-naive, including 59 in cohort 1 and 70 in cohort 2. At baseline, 15% had unfavorable cytogenetics, 52% had neuropathy, and two-thirds were refractory to their most recent therapy.

The overall response rate was 42% in cohort 1 and 52% in cohort 2, Dr. Vij reported. The median time to disease progression was 8.3 months and median duration of response was 13.1 months in cohort 1. Neither end point had been reached in cohort 2.

Dr. Vij noted that the higher response rates in cohort 2 do not appear to be associated with higher side effects. Mild to moderate peripheral neuropathy was reported in 14% of cohort 1 and 19% of cohort 2. Only one case of grade-3 peripheral neuropathy was reported in cohort 1 and none in cohort 2.

The most common adverse events in cohort 1 and cohort 2, respectively, were fatigue (71%, 54%), nausea (54%, 44%), anemia (46%, 39%), dyspnea (49%, 30%), cough (39%, 30%) and pyrexia (36%, 33%). The majority were grade 1/2; adverse events leading to carfilzomib discontinuation occurred in 22% of cohort 1 and 10% of cohort 2, he said.

These data are suggestive of a dose-response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007, Dr. Vij said.

The trials were sponsored by Onyx Pharmaceuticals. Dr. Jakubowiak and his coauthors and Dr. Vij and his coauthors reported financial relationships with several pharmaceutical firms, including Onyx.

SAN DIEGO – Adding the investigational protease inhibitor carfilzomib to lenalidomide and low-dose dexamethasone produced responses comparable with those achieved with the best frontline regimens in multiple myeloma, final results from a multicenter phase I/II study indicate.

Nearly all, 94%, of 49 evaluable patients with newly diagnosed multiple myeloma achieved at least a partial response with the triple combination, and 53% attained a near complete, complete, or stringent complete response (nCR/CR/sCR).

Responses also continued to improve with time, with 79% of patients reaching a nCR/CR/sCR after 12 cycles, Dr. Andrzej J. Jakubowiak reported at the annual meeting of the American Society of Hematology on behalf of the Multiple Myeloma Research Consortium. Although the data are still being evaluated, about half of the nCR/CR/sCRs were complete responses.

"These response rates appear to compare favorably to the best frontline regimens in myeloma and, I would dare to say, they compare favorably to treatment sequences with transplant," said Dr. Jakubowiak, director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone previously posted an encouraging overall response rate of 78% and a nCR/CR rate of 40% with a low toxicity profile in the relapsed and/or refractory setting, providing the rationale for two ongoing phase III trials. The ASPIRE trial is evaluating lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma; the FOCUS trial, to support registration in Europe, is evaluating single-agent carfilzomib in relapsed/refractory myeloma.

Onyx Pharmaceuticals has announced that the U.S. Food and Drug Administration is giving carfilzomib a standard review in the treatment of relapsed and refractory myeloma, with a decision expected by July 27.

An expanded access program is also underway in partnership with the Multiple Myeloma Research Foundation for eligible patients in the United States with relapsed and refractory myeloma for whom no satisfactory treatment alternatives are available.

The carfilzomib, lenalidomide, and dexamethasone (CRd) regimen was one of several (including such novel therapies as oral MLN9708 protease inhibitor and the so-called BiRD regimen of clarithromycin [Biaxin] with lenalidomide and dexamethasone) for which impressive results were reported at the ASH meeting. "All of these drugs will find their own place" Dr. Jakubowiak said, but, he added, CRd is "the strongest regimen I’ve used, and I’ve used a variety of these regimens."

He noted that his patients continue to come to the clinic with no complaints of toxicity and that their responses continue to improve, providing further stimulus for those trying to sort through the abundance of novel myeloma therapies.

The current study included 53 patients who were eligible or ineligible for transplant: they received eight cycles of induction therapy with IV carfilzomib 20, 27, or 36 mg/m²; oral lenalidomide 25 mg, and oral dexamethasone at 40 mg for cycles 1-4 and at 20 mg for cycles 5-8, followed by maintenance therapy at the doses tolerated at the end of the eight cycles until disease progression or toxicity. Patients with at least a partial response after four cycles could proceed to stem cell transplant.

Their median age was 59 years, and 60% had advanced myeloma and 33% had unfavorable cytogenetics including deletion 17p.

After a median of 9.5 months follow-up, only one patient progressed and all patients were alive. Of these, 88% of patients remained on treatment, and 24 of 27 patients who began maintenance therapy continued on CRd maintenance, said Dr. Jakubowiak.

Dose modifications were required in 16 patients, and one patient discontinued therapy because of toxicity. Peripheral neuropathy was reported in almost one-quarter of patients, but all cases were grade 1/2. Dyspnea was reported in about one-third of patients, but it was quickly resolving, he noted.

Responses in the 16 patients with unfavorable cytogenetics were similar to all other patients, and included at least a partial response in 100% and nCR/CR/sCR in 56%, Dr. Jakubowiak said.

Dr. Ravi Vij of Washington University, St. Louis, presented final results of single-agent carfilzomib in bortezomib (Velcade)-naive patients in the separate phase II PX-171-004 study in myeloma that had relapsed after one to three lines of therapy.

The trial enrolled 165 patients, with one cohort receiving IV carfilzomib 20 mg/m² for all 12 cycles and the second cohort given carfilzomib 20 mg/m² for cycle 1 with escalation to 27 mg/m² in all subsequent cycles.

A total of 129 patients were bortezomib-naive, including 59 in cohort 1 and 70 in cohort 2. At baseline, 15% had unfavorable cytogenetics, 52% had neuropathy, and two-thirds were refractory to their most recent therapy.

The overall response rate was 42% in cohort 1 and 52% in cohort 2, Dr. Vij reported. The median time to disease progression was 8.3 months and median duration of response was 13.1 months in cohort 1. Neither end point had been reached in cohort 2.

Dr. Vij noted that the higher response rates in cohort 2 do not appear to be associated with higher side effects. Mild to moderate peripheral neuropathy was reported in 14% of cohort 1 and 19% of cohort 2. Only one case of grade-3 peripheral neuropathy was reported in cohort 1 and none in cohort 2.

The most common adverse events in cohort 1 and cohort 2, respectively, were fatigue (71%, 54%), nausea (54%, 44%), anemia (46%, 39%), dyspnea (49%, 30%), cough (39%, 30%) and pyrexia (36%, 33%). The majority were grade 1/2; adverse events leading to carfilzomib discontinuation occurred in 22% of cohort 1 and 10% of cohort 2, he said.

These data are suggestive of a dose-response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007, Dr. Vij said.

The trials were sponsored by Onyx Pharmaceuticals. Dr. Jakubowiak and his coauthors and Dr. Vij and his coauthors reported financial relationships with several pharmaceutical firms, including Onyx.

SAN DIEGO – The combination of vorinostat and bortezomib produced mixed results for patients with relapsed or refractory multiple myeloma in two pivotal international trials.

Heavily pretreated patients achieved durable responses and an unprecedented survival advantage in the phase IIB Vantage 095 trial, whereas survival gains were less impressive among pretreated patients who remained sensitive to bortezomib (Velcade) in the phase III Vantage 088 trial. Findings from both trials were presented at the annual meeting of the American Society of Hematology.

"I think this kind of combination of the histone deacetylase [HDAC] inhibitor vorinostat and bortezomib offers a very important option in patients who really have no other conventional therapeutic alternatives," said Dr. David S. Siegel, lead author of the Vantage 095 trial and division chief for myeloma at the Hackensack (N.J.) University Medical Center.

Vorinostat (Zolinza) has been approved since 2006 for the treatment of cutaneous T-cell lymphoma, and is under investigation in a variety of other cancers. Phase II trials of vorinostat, lenalidomide (Revlimid), and dexamethasone are underway or planned in myeloma patients who are refractory to lenalidomide-containing regimens or have relapsed on lenalidomide maintenance therapy.

Dr. Siegel said in an interview that vorinostat does not have intrinsic activity, but that HDAC inhibitors resensitize patients by dampening the changes involved in drug resistance. Whether Merck will file for an additional indication for vorinostat based on the current Vantage data is unclear, but Dr. Siegel suggested that the drug could play a key role in overcoming resistance to lenalidomide, bortezomib, and pomalidomide (a promising investigational immunomodulatory drug, or IMiD) as the use of these agents increases.

"It [vorinostat] has sort of been reserved for the last-ditch effort, with extraordinary success ... and no drugs in the myeloma space work in that last-ditch effort better than vorinostat in my hands," he said.

Vantage 095: Refractory Patients

According to final results from the phase IIB Vantage 095 trial involving 142 patients whose disease was described as refractory to basically all available therapies, 17% achieved at least a partial response and 77% achieved disease control.

Responses to vorinostat and bortezomib were sustainable, and in some cases particularly durable, said Dr. Siegel. The median duration of response was 6.3 months. Applying the EBMT (European Group for Blood and Marrow Transplantation) criteria, the median duration was 7.0 months and the overall response rate 11%.

The 2-year overall survival rate was 32%, and median overall survival was 11.1 months. Dr. Siegel noted that a median of roughly 4.5 months occurred from the time when patients were considered refractory to prior bortezomib and an IMiD to the time when they came on trial. He said the survival benchmark for such dual-refractory patients is 8.8 months.

The doublet was described as generally well tolerated, with 27% of patients completing at least eight cycles. Serious adverse events were reported in 65% of patients, but only 11% of treatment discontinuations resulted from serious adverse events. Neuropathy and febrile neutropenia were reported in 2% and 4%, respectively. One patient died because of an adverse event that was considered possibly or probably drug related.

Patients received oral vorinostat 400 mg/day on days 1-14 plus bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease or no change after four cycles could receive oral dexamethasone 20 mg on the day of and day after each dose of bortezomib.

The trial enrolled patients with relapsed and refractory disease who had received at least two prior lines of therapy, and were refractory to bortezomib and ineligible for or refractory to at least one IMiD. Their median age was 63 years, and 69% had received at least four prior lines of therapy (range, 2-17 lines).

Subgroup analyses revealed that partial responses occurred in 18% of patients who were refractory to a bortezomib regimen and 22% who were refractory to up to two IMiDs. Overall survival was 11.7 months and 11.2 months, respectively. Progression-free survival for the entire cohort was 3.13 months.

Session comoderator Prof. Michele Cavo of the University of Bologna (Italy) said the most important message of the trial was the 11-month median overall survival. "This combination may offer a chance to patients heavily pretreated, almost 100% of them with prior refractoriness to bortezomib and lenalidomide and [other] IMiDs," he said in an interview. "This means that the combination of a histone deacetylase inhibitor with bortezomib may partially overcome prior refractoriness to a proteasome inhibitor or an IMiD."

Clinicians will need to figure out how best to use vorinostat, but Dr. Siegel and Dr. Cavo agreed that its oral administration is a big advantage, particularly for patients with advanced-stage disease, who are often elderly and in pain.

Vantage 088: In Bortezomib Sensitive

Dr. Meletios Dimopoulos presented data from the randomized phase III Vantage 088 trial involving 637 patients who had progressive disease after one to three prior treatments, but were bortezomib sensitive. Patients were randomized to the same combination regimen that was used in Vantage 095, or to vorinostat 400 mg/day on days 1-14 plus placebo.

The combination of bortezomib plus vorinostat increased the primary end point of progression-free survival from 6.83 months to 7.63 months (hazard ratio, 0.774; P = .01). Although the difference reached statistical significance, the audience questioned the clinical significance of a 25-day advantage, and pointed out that this was the very first salvage line for 45% of patients in the bortezomib/vorinostat arm vs. 40% in the control arm. In addition, median overall survival was not significantly different between the bortezomib/vorinostat and control arms.

Dr. Dimopoulos responded that Vantage 088 was indeed a positive trial because one in five patients benefited from the combination. "If vorinostat is approved for the use of myeloma, it is sure that we will find better ways to use it, as is the case with bortezomib today," he said.

Using EBMT criteria, the combination of vorinostat plus bortezomib significantly improved the overall response (56% vs. 41%) and clinical benefit rates (71% vs. 53%), compared with bortezomib alone (both P less than .0001). Duration of response by EBMT criteria was similar at 8.5 months and 8.4 months, respectively, reported Dr. Dimopoulos of the department of clinical therapeutics at the National and Kapodistrian University of Athens.

Subgroup analyses revealed no significant differences between the two arms in overall response or progression-free survival based on age, type of melanoma, number of previous lines of therapy, or prior exposure to IMiDs or bortezomib.

At baseline, 46% of the 317 patients in the bortezomib/vorinostat arm and 48% of the 320 patients in the bortezomib/placebo arm were nonresponsive to their last line of therapy.

Dr. Siegel reported receiving research funding and honoraria and serving as a speaker for Millennium Pharmaceuticals and honoraria from Merck. His coauthors reported financial relationships with several firms including Millennium, Merck, and Novartis. Dr. Dimopoulos reported consultancy and honoraria from Celgene and Ortho-Biotech. His coauthors reported relationships with multiple pharmaceutical firms.

SAN DIEGO – The combination of vorinostat and bortezomib produced mixed results for patients with relapsed or refractory multiple myeloma in two pivotal international trials.

Heavily pretreated patients achieved durable responses and an unprecedented survival advantage in the phase IIB Vantage 095 trial, whereas survival gains were less impressive among pretreated patients who remained sensitive to bortezomib (Velcade) in the phase III Vantage 088 trial. Findings from both trials were presented at the annual meeting of the American Society of Hematology.

"I think this kind of combination of the histone deacetylase [HDAC] inhibitor vorinostat and bortezomib offers a very important option in patients who really have no other conventional therapeutic alternatives," said Dr. David S. Siegel, lead author of the Vantage 095 trial and division chief for myeloma at the Hackensack (N.J.) University Medical Center.

Vorinostat (Zolinza) has been approved since 2006 for the treatment of cutaneous T-cell lymphoma, and is under investigation in a variety of other cancers. Phase II trials of vorinostat, lenalidomide (Revlimid), and dexamethasone are underway or planned in myeloma patients who are refractory to lenalidomide-containing regimens or have relapsed on lenalidomide maintenance therapy.

Dr. Siegel said in an interview that vorinostat does not have intrinsic activity, but that HDAC inhibitors resensitize patients by dampening the changes involved in drug resistance. Whether Merck will file for an additional indication for vorinostat based on the current Vantage data is unclear, but Dr. Siegel suggested that the drug could play a key role in overcoming resistance to lenalidomide, bortezomib, and pomalidomide (a promising investigational immunomodulatory drug, or IMiD) as the use of these agents increases.

"It [vorinostat] has sort of been reserved for the last-ditch effort, with extraordinary success ... and no drugs in the myeloma space work in that last-ditch effort better than vorinostat in my hands," he said.

Vantage 095: Refractory Patients

According to final results from the phase IIB Vantage 095 trial involving 142 patients whose disease was described as refractory to basically all available therapies, 17% achieved at least a partial response and 77% achieved disease control.

Responses to vorinostat and bortezomib were sustainable, and in some cases particularly durable, said Dr. Siegel. The median duration of response was 6.3 months. Applying the EBMT (European Group for Blood and Marrow Transplantation) criteria, the median duration was 7.0 months and the overall response rate 11%.

The 2-year overall survival rate was 32%, and median overall survival was 11.1 months. Dr. Siegel noted that a median of roughly 4.5 months occurred from the time when patients were considered refractory to prior bortezomib and an IMiD to the time when they came on trial. He said the survival benchmark for such dual-refractory patients is 8.8 months.

The doublet was described as generally well tolerated, with 27% of patients completing at least eight cycles. Serious adverse events were reported in 65% of patients, but only 11% of treatment discontinuations resulted from serious adverse events. Neuropathy and febrile neutropenia were reported in 2% and 4%, respectively. One patient died because of an adverse event that was considered possibly or probably drug related.

Patients received oral vorinostat 400 mg/day on days 1-14 plus bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease or no change after four cycles could receive oral dexamethasone 20 mg on the day of and day after each dose of bortezomib.

The trial enrolled patients with relapsed and refractory disease who had received at least two prior lines of therapy, and were refractory to bortezomib and ineligible for or refractory to at least one IMiD. Their median age was 63 years, and 69% had received at least four prior lines of therapy (range, 2-17 lines).

Subgroup analyses revealed that partial responses occurred in 18% of patients who were refractory to a bortezomib regimen and 22% who were refractory to up to two IMiDs. Overall survival was 11.7 months and 11.2 months, respectively. Progression-free survival for the entire cohort was 3.13 months.

Session comoderator Prof. Michele Cavo of the University of Bologna (Italy) said the most important message of the trial was the 11-month median overall survival. "This combination may offer a chance to patients heavily pretreated, almost 100% of them with prior refractoriness to bortezomib and lenalidomide and [other] IMiDs," he said in an interview. "This means that the combination of a histone deacetylase inhibitor with bortezomib may partially overcome prior refractoriness to a proteasome inhibitor or an IMiD."

Clinicians will need to figure out how best to use vorinostat, but Dr. Siegel and Dr. Cavo agreed that its oral administration is a big advantage, particularly for patients with advanced-stage disease, who are often elderly and in pain.

Vantage 088: In Bortezomib Sensitive

Dr. Meletios Dimopoulos presented data from the randomized phase III Vantage 088 trial involving 637 patients who had progressive disease after one to three prior treatments, but were bortezomib sensitive. Patients were randomized to the same combination regimen that was used in Vantage 095, or to vorinostat 400 mg/day on days 1-14 plus placebo.

The combination of bortezomib plus vorinostat increased the primary end point of progression-free survival from 6.83 months to 7.63 months (hazard ratio, 0.774; P = .01). Although the difference reached statistical significance, the audience questioned the clinical significance of a 25-day advantage, and pointed out that this was the very first salvage line for 45% of patients in the bortezomib/vorinostat arm vs. 40% in the control arm. In addition, median overall survival was not significantly different between the bortezomib/vorinostat and control arms.

Dr. Dimopoulos responded that Vantage 088 was indeed a positive trial because one in five patients benefited from the combination. "If vorinostat is approved for the use of myeloma, it is sure that we will find better ways to use it, as is the case with bortezomib today," he said.

Using EBMT criteria, the combination of vorinostat plus bortezomib significantly improved the overall response (56% vs. 41%) and clinical benefit rates (71% vs. 53%), compared with bortezomib alone (both P less than .0001). Duration of response by EBMT criteria was similar at 8.5 months and 8.4 months, respectively, reported Dr. Dimopoulos of the department of clinical therapeutics at the National and Kapodistrian University of Athens.

Subgroup analyses revealed no significant differences between the two arms in overall response or progression-free survival based on age, type of melanoma, number of previous lines of therapy, or prior exposure to IMiDs or bortezomib.

At baseline, 46% of the 317 patients in the bortezomib/vorinostat arm and 48% of the 320 patients in the bortezomib/placebo arm were nonresponsive to their last line of therapy.

Dr. Siegel reported receiving research funding and honoraria and serving as a speaker for Millennium Pharmaceuticals and honoraria from Merck. His coauthors reported financial relationships with several firms including Millennium, Merck, and Novartis. Dr. Dimopoulos reported consultancy and honoraria from Celgene and Ortho-Biotech. His coauthors reported relationships with multiple pharmaceutical firms.

SAN DIEGO – The combination of vorinostat and bortezomib produced mixed results for patients with relapsed or refractory multiple myeloma in two pivotal international trials.

Heavily pretreated patients achieved durable responses and an unprecedented survival advantage in the phase IIB Vantage 095 trial, whereas survival gains were less impressive among pretreated patients who remained sensitive to bortezomib (Velcade) in the phase III Vantage 088 trial. Findings from both trials were presented at the annual meeting of the American Society of Hematology.

"I think this kind of combination of the histone deacetylase [HDAC] inhibitor vorinostat and bortezomib offers a very important option in patients who really have no other conventional therapeutic alternatives," said Dr. David S. Siegel, lead author of the Vantage 095 trial and division chief for myeloma at the Hackensack (N.J.) University Medical Center.

Vorinostat (Zolinza) has been approved since 2006 for the treatment of cutaneous T-cell lymphoma, and is under investigation in a variety of other cancers. Phase II trials of vorinostat, lenalidomide (Revlimid), and dexamethasone are underway or planned in myeloma patients who are refractory to lenalidomide-containing regimens or have relapsed on lenalidomide maintenance therapy.

Dr. Siegel said in an interview that vorinostat does not have intrinsic activity, but that HDAC inhibitors resensitize patients by dampening the changes involved in drug resistance. Whether Merck will file for an additional indication for vorinostat based on the current Vantage data is unclear, but Dr. Siegel suggested that the drug could play a key role in overcoming resistance to lenalidomide, bortezomib, and pomalidomide (a promising investigational immunomodulatory drug, or IMiD) as the use of these agents increases.

"It [vorinostat] has sort of been reserved for the last-ditch effort, with extraordinary success ... and no drugs in the myeloma space work in that last-ditch effort better than vorinostat in my hands," he said.

Vantage 095: Refractory Patients

According to final results from the phase IIB Vantage 095 trial involving 142 patients whose disease was described as refractory to basically all available therapies, 17% achieved at least a partial response and 77% achieved disease control.

Responses to vorinostat and bortezomib were sustainable, and in some cases particularly durable, said Dr. Siegel. The median duration of response was 6.3 months. Applying the EBMT (European Group for Blood and Marrow Transplantation) criteria, the median duration was 7.0 months and the overall response rate 11%.

The 2-year overall survival rate was 32%, and median overall survival was 11.1 months. Dr. Siegel noted that a median of roughly 4.5 months occurred from the time when patients were considered refractory to prior bortezomib and an IMiD to the time when they came on trial. He said the survival benchmark for such dual-refractory patients is 8.8 months.

The doublet was described as generally well tolerated, with 27% of patients completing at least eight cycles. Serious adverse events were reported in 65% of patients, but only 11% of treatment discontinuations resulted from serious adverse events. Neuropathy and febrile neutropenia were reported in 2% and 4%, respectively. One patient died because of an adverse event that was considered possibly or probably drug related.

Patients received oral vorinostat 400 mg/day on days 1-14 plus bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease or no change after four cycles could receive oral dexamethasone 20 mg on the day of and day after each dose of bortezomib.

The trial enrolled patients with relapsed and refractory disease who had received at least two prior lines of therapy, and were refractory to bortezomib and ineligible for or refractory to at least one IMiD. Their median age was 63 years, and 69% had received at least four prior lines of therapy (range, 2-17 lines).

Subgroup analyses revealed that partial responses occurred in 18% of patients who were refractory to a bortezomib regimen and 22% who were refractory to up to two IMiDs. Overall survival was 11.7 months and 11.2 months, respectively. Progression-free survival for the entire cohort was 3.13 months.

Session comoderator Prof. Michele Cavo of the University of Bologna (Italy) said the most important message of the trial was the 11-month median overall survival. "This combination may offer a chance to patients heavily pretreated, almost 100% of them with prior refractoriness to bortezomib and lenalidomide and [other] IMiDs," he said in an interview. "This means that the combination of a histone deacetylase inhibitor with bortezomib may partially overcome prior refractoriness to a proteasome inhibitor or an IMiD."

Clinicians will need to figure out how best to use vorinostat, but Dr. Siegel and Dr. Cavo agreed that its oral administration is a big advantage, particularly for patients with advanced-stage disease, who are often elderly and in pain.

Vantage 088: In Bortezomib Sensitive

Dr. Meletios Dimopoulos presented data from the randomized phase III Vantage 088 trial involving 637 patients who had progressive disease after one to three prior treatments, but were bortezomib sensitive. Patients were randomized to the same combination regimen that was used in Vantage 095, or to vorinostat 400 mg/day on days 1-14 plus placebo.

The combination of bortezomib plus vorinostat increased the primary end point of progression-free survival from 6.83 months to 7.63 months (hazard ratio, 0.774; P = .01). Although the difference reached statistical significance, the audience questioned the clinical significance of a 25-day advantage, and pointed out that this was the very first salvage line for 45% of patients in the bortezomib/vorinostat arm vs. 40% in the control arm. In addition, median overall survival was not significantly different between the bortezomib/vorinostat and control arms.

Dr. Dimopoulos responded that Vantage 088 was indeed a positive trial because one in five patients benefited from the combination. "If vorinostat is approved for the use of myeloma, it is sure that we will find better ways to use it, as is the case with bortezomib today," he said.

Using EBMT criteria, the combination of vorinostat plus bortezomib significantly improved the overall response (56% vs. 41%) and clinical benefit rates (71% vs. 53%), compared with bortezomib alone (both P less than .0001). Duration of response by EBMT criteria was similar at 8.5 months and 8.4 months, respectively, reported Dr. Dimopoulos of the department of clinical therapeutics at the National and Kapodistrian University of Athens.

Subgroup analyses revealed no significant differences between the two arms in overall response or progression-free survival based on age, type of melanoma, number of previous lines of therapy, or prior exposure to IMiDs or bortezomib.

At baseline, 46% of the 317 patients in the bortezomib/vorinostat arm and 48% of the 320 patients in the bortezomib/placebo arm were nonresponsive to their last line of therapy.

Dr. Siegel reported receiving research funding and honoraria and serving as a speaker for Millennium Pharmaceuticals and honoraria from Merck. His coauthors reported financial relationships with several firms including Millennium, Merck, and Novartis. Dr. Dimopoulos reported consultancy and honoraria from Celgene and Ortho-Biotech. His coauthors reported relationships with multiple pharmaceutical firms.

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

To listen to a podcast concerning the brentuximab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

To listen to a podcast concerning the brentuximab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

To listen to a podcast concerning the brentuximab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.

Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.

All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).

The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.

Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.

Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.

"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.

Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.

Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.

He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.

Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).

Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.

The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).

A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).

Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.

All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.

Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.

"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.

Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.

Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.

There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.

One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.

Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.

The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.

Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.

The study was funded by the participating centers. The authors reported no relevant conflicts of interest.

SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.

Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.

All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).

The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.

Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.

Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.

"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.

Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.

Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.

He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.

Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).

Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.

The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).

A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).

Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.

All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.

Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.

"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.

Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.

Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.

There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.

One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.

Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.

The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.

Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.

The study was funded by the participating centers. The authors reported no relevant conflicts of interest.

SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.

Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.

All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).

The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.

Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.

Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.

"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.

Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.

Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.

He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.

Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).

Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.

The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).

A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).

Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.

All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.

Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.

"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.

Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.

Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.

There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.

One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.

Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.

The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.

Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.

The study was funded by the participating centers. The authors reported no relevant conflicts of interest.

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.

SAN DIEGO – A simple scoring system identified a subset of young patients with Hodgkin’s lymphoma who are predicted to have an event-free survival rate of less than 80%.

The system, known as the Childhood Hodgkin International Prognostic Score (CHIPS), found that four factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever, Dr. Cindy L. Schwartz reported during a poster session at the annual meeting of the American Society of Hematology.

She and her associates with the Children’s Oncology Group evaluated 1,721 patients with intermediate risk Hodgkin’s lymphoma who were younger than age 21 and treated on AHOD0031: a phase III study of dose-intensive therapy.

The current study involved tailoring treatment by early response in 770 patients who were randomized or assigned to receive the same treatment (four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) and 21 Gy involved field radiotherapy (IFRT).

According to Dr. Schwartz, director of the division of pediatric hematology/oncology at Hasbro Children’s Hospital, Providence, R.I., rapid early response was defined as a two-dimensional tumor reduction of greater than 60% on CT after two cycles of ABVE-PC. Complete response was defined as a greater than 80% two-dimensional reduction by CT, and resolution of nuclear imaging abnormalities.

Rapid responders who achieved complete response after two additional ABVE-PC treatments were randomized to receive 21 Gy radiation. Slow early responders were randomized to receive dexamethasone, etoposide, cisplatin, and cytarabine (DECA) in addition to the four ABVE-PC treatments and 21 Gy radiation treatment.

Using Cox regression analysis and multivariable predictive modeling, the researchers identified four predictors of event-free survival: stage IV disease (hazard ratio, 1.6), mediastinal adenopathy (HR 1.7), albumin of less than 3.5 g/dL (HR 1.8), and fever (HR 2.5).

Because the hazard ratios were similar, the researchers devised the CHIPS score, which gave one point for each of the four adverse predictors. Using this approach, they determined that the event-free survival rate was 90% for patients with a CHIPS score of 0 or 1, 78% for those with a CHIPS score of 2, and 62% for those with a CHIPS score of 3. (Because the study enrolled only patients with intermediate-risk disease, no one had a CHIPS score of 4.) From this they determined that 22% of an intermediate-risk population can be predicted to have an event-free survival rate of less than 80%.

"Now that we know who’s a good responder to initial chemotherapy, we’re going to try and change their treatment much earlier than we have been able to previously," Dr. Schwartz said in an interview. "The next thing to do is analyze some of the biologic factors that contribute to their response rate."

Studies of CHIPS in additional cohorts of newly diagnosed patients are also planned, she said.

Dr. Schwartz said that she had no relevant financial disclosures to make.

SAN DIEGO – A simple scoring system identified a subset of young patients with Hodgkin’s lymphoma who are predicted to have an event-free survival rate of less than 80%.

The system, known as the Childhood Hodgkin International Prognostic Score (CHIPS), found that four factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever, Dr. Cindy L. Schwartz reported during a poster session at the annual meeting of the American Society of Hematology.

She and her associates with the Children’s Oncology Group evaluated 1,721 patients with intermediate risk Hodgkin’s lymphoma who were younger than age 21 and treated on AHOD0031: a phase III study of dose-intensive therapy.

The current study involved tailoring treatment by early response in 770 patients who were randomized or assigned to receive the same treatment (four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) and 21 Gy involved field radiotherapy (IFRT).

According to Dr. Schwartz, director of the division of pediatric hematology/oncology at Hasbro Children’s Hospital, Providence, R.I., rapid early response was defined as a two-dimensional tumor reduction of greater than 60% on CT after two cycles of ABVE-PC. Complete response was defined as a greater than 80% two-dimensional reduction by CT, and resolution of nuclear imaging abnormalities.

Rapid responders who achieved complete response after two additional ABVE-PC treatments were randomized to receive 21 Gy radiation. Slow early responders were randomized to receive dexamethasone, etoposide, cisplatin, and cytarabine (DECA) in addition to the four ABVE-PC treatments and 21 Gy radiation treatment.

Using Cox regression analysis and multivariable predictive modeling, the researchers identified four predictors of event-free survival: stage IV disease (hazard ratio, 1.6), mediastinal adenopathy (HR 1.7), albumin of less than 3.5 g/dL (HR 1.8), and fever (HR 2.5).

Because the hazard ratios were similar, the researchers devised the CHIPS score, which gave one point for each of the four adverse predictors. Using this approach, they determined that the event-free survival rate was 90% for patients with a CHIPS score of 0 or 1, 78% for those with a CHIPS score of 2, and 62% for those with a CHIPS score of 3. (Because the study enrolled only patients with intermediate-risk disease, no one had a CHIPS score of 4.) From this they determined that 22% of an intermediate-risk population can be predicted to have an event-free survival rate of less than 80%.

"Now that we know who’s a good responder to initial chemotherapy, we’re going to try and change their treatment much earlier than we have been able to previously," Dr. Schwartz said in an interview. "The next thing to do is analyze some of the biologic factors that contribute to their response rate."

Studies of CHIPS in additional cohorts of newly diagnosed patients are also planned, she said.

Dr. Schwartz said that she had no relevant financial disclosures to make.

SAN DIEGO – A simple scoring system identified a subset of young patients with Hodgkin’s lymphoma who are predicted to have an event-free survival rate of less than 80%.

The system, known as the Childhood Hodgkin International Prognostic Score (CHIPS), found that four factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever, Dr. Cindy L. Schwartz reported during a poster session at the annual meeting of the American Society of Hematology.

She and her associates with the Children’s Oncology Group evaluated 1,721 patients with intermediate risk Hodgkin’s lymphoma who were younger than age 21 and treated on AHOD0031: a phase III study of dose-intensive therapy.

The current study involved tailoring treatment by early response in 770 patients who were randomized or assigned to receive the same treatment (four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) and 21 Gy involved field radiotherapy (IFRT).

According to Dr. Schwartz, director of the division of pediatric hematology/oncology at Hasbro Children’s Hospital, Providence, R.I., rapid early response was defined as a two-dimensional tumor reduction of greater than 60% on CT after two cycles of ABVE-PC. Complete response was defined as a greater than 80% two-dimensional reduction by CT, and resolution of nuclear imaging abnormalities.

Rapid responders who achieved complete response after two additional ABVE-PC treatments were randomized to receive 21 Gy radiation. Slow early responders were randomized to receive dexamethasone, etoposide, cisplatin, and cytarabine (DECA) in addition to the four ABVE-PC treatments and 21 Gy radiation treatment.

Using Cox regression analysis and multivariable predictive modeling, the researchers identified four predictors of event-free survival: stage IV disease (hazard ratio, 1.6), mediastinal adenopathy (HR 1.7), albumin of less than 3.5 g/dL (HR 1.8), and fever (HR 2.5).

Because the hazard ratios were similar, the researchers devised the CHIPS score, which gave one point for each of the four adverse predictors. Using this approach, they determined that the event-free survival rate was 90% for patients with a CHIPS score of 0 or 1, 78% for those with a CHIPS score of 2, and 62% for those with a CHIPS score of 3. (Because the study enrolled only patients with intermediate-risk disease, no one had a CHIPS score of 4.) From this they determined that 22% of an intermediate-risk population can be predicted to have an event-free survival rate of less than 80%.

"Now that we know who’s a good responder to initial chemotherapy, we’re going to try and change their treatment much earlier than we have been able to previously," Dr. Schwartz said in an interview. "The next thing to do is analyze some of the biologic factors that contribute to their response rate."

Studies of CHIPS in additional cohorts of newly diagnosed patients are also planned, she said.

Dr. Schwartz said that she had no relevant financial disclosures to make.