Phase II Results Continue to Support Carfilzomib in Myeloma

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.