Vorinostat Delivers Mixed Results in Multiple Myeloma

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.