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Ibrutinib may prove useful in MM, research shows

Bone marrow aspirate

showing multiple myeloma

NEW YORK—Results of an open-label, phase 2, dose-escalation study of ibrutinib combined with low-dose dexamethasone suggest the Bruton’s tyrosine kinase (BTK) inhibitor may be useful in treating relapsed or relapsed and refractory patients with multiple myeloma (MM).

In the highest dose cohort, 23% of patients experienced a clinical benefit, which was defined as a minimal response or better by International Myeloma Working Group criteria.

“Ibrutinib is a remarkable agent and, through BTK inhibition, has been a game-changer in CLL [chronic lymphocytic leukemia],” said Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Richardson reported results with ibrutinib in MM at Lymphoma & Myeloma 2015.

The rationale for the use of ibrutinib in myeloma is the robust BTK expression in the plasma cells of MM patients as well as its regulation of myeloma “stemness” in the bone marrow.

Ibrutinib plus low-dose dexamethasone has previously demonstrated activity in myeloma at the highest dose tested in a phase 1 trial.

So investigators continued to evaluate ibrutinib in 4 dose cohorts, with and without dexamathesone, and enrolled 92 relapsed/refractory MM patients. Dr Richardson described the results of cohort 4, which met criteria for expansion as of March 2015.

The investigators enrolled 43 patients in cohort 4 to receive 840 mg daily of ibrutinib plus 40 mg of dexamethasone weekly. This dose of ibrutinib is double the dose approved by the US Food and Drug Administration (FDA) for treatment of CLL and Waldenström’s macroglobulinemia.

The patient population was “very typical” for a relapsed/refractory patient population, Dr Richardson noted. The median age was 65 years (range, 43–81), almost two-thirds were male, and they had a median of 4 (range, 2–10) prior therapies.

More than half of patients had an ECOG performance status of 0 or 1, and their median time since diagnosis was 6.5 years.

Nineteen percent had t(11;14), and other chromosomal abnormalities included del 13q14, t(4:14), and del 17p. Twenty-three patients were ISS stage I, 16 were ISS stage II, and 4 were ISS stage III.

Seventy-seven percent of patients had received an autologous stem cell transplant, 95% had prior alkylator treatment, 91% prior lenalidomide, 58% prior thalidomide, and 91% prior bortezomib treatment.

All patients were steroid-refractory. Thirty-five percent were refractory to alkylator treatment, 61% were refractory to lenalidomide, and 49% were refractory to bortezomib.

“And even a number of them had been exposed to pomalidomide and also to carfilzomib,” Dr Richardson said, “recognizing that these are the new and exciting drugs on the block, but, at the same time, a significant number of our patients already received those therapies.”

Five percent of patients achieved a partial response to ibrutinib and low-dose dexamethasone, and 18% achieved a minimal response, for a clinical benefit rate of 23%. Thirty percent had stable disease after 4 or more cycles.

“What was particularly striking,” Dr Richardson said, “was at the top dose, the 840-mg dose, the progression-free survival.”

The median time to disease progression was 5.4 months (range, 0.0–16.4), which the investigators thought was compelling in this large study.

Dr Richardson noted that there were no significant differences in safety observed across all dose cohorts, although 55% of patients experienced a grade 3 or greater treatment-emergent adverse event (AE), while 29% experienced at least 1 serious AE. And 10% of patients experienced peripheral neuropathy (PN), 8 of whom had a prior history of PN.

Treatment-emergent hematologic AEs of any grade in cohort 4 occurring in more than 20% of patients included anemia (23%) and thrombocytopenia (21%). Grade 3/4 anemia and thrombocytopenia occurred in 9% of patients in each category.

 

 

Treatment-emergent non-hematologic AEs of any grade in cohort 4 occurring in more than 20% of patients included diarrhea (63%), fatigue (49%), cough (26%), nausea (23%), and muscle spasms (21%). Two percent of patients had grade 3/4 diarrhea. There were no other grade 3/4 adverse events in the cohort.

Eighty-six percent of patients in cohort 4 discontinued treatment, 60% due to progressive disease, 12% due to an AE, and 2% at the discretion of the investigator. Twelve percent withdrew, were noncompliant, or required concomitant medication that was not permitted by the protocol.

Overall, Dr Richardson said, the safety profile was manageable, similar across the dosing cohorts, and consistent with those seen in CLL and Waldenström’s macroglobulinemia. The 840-mg dose did not increase toxicity and demonstrated activity in this heavily pretreated population.

“The real signal that struck us,” Dr Richardson emphasized, “was the progression-free survival at 5.4 months . . . for a 92-patient, multicenter experience, this is obviously, I think, an encouraging start.”

Investigators continue to explore ibrutinib in 2 ongoing combination studies, one with carfilzomib and dexamethasone (PCYC-1119) and another with pomalidomide and dexamethasone (PCYC-1138). Another trial with lenalidomide and dexamethasone is planned.

Ibrutinib now has 4 FDA-approved indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.

Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.

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Bone marrow aspirate

showing multiple myeloma

NEW YORK—Results of an open-label, phase 2, dose-escalation study of ibrutinib combined with low-dose dexamethasone suggest the Bruton’s tyrosine kinase (BTK) inhibitor may be useful in treating relapsed or relapsed and refractory patients with multiple myeloma (MM).

In the highest dose cohort, 23% of patients experienced a clinical benefit, which was defined as a minimal response or better by International Myeloma Working Group criteria.

“Ibrutinib is a remarkable agent and, through BTK inhibition, has been a game-changer in CLL [chronic lymphocytic leukemia],” said Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Richardson reported results with ibrutinib in MM at Lymphoma & Myeloma 2015.

The rationale for the use of ibrutinib in myeloma is the robust BTK expression in the plasma cells of MM patients as well as its regulation of myeloma “stemness” in the bone marrow.

Ibrutinib plus low-dose dexamethasone has previously demonstrated activity in myeloma at the highest dose tested in a phase 1 trial.

So investigators continued to evaluate ibrutinib in 4 dose cohorts, with and without dexamathesone, and enrolled 92 relapsed/refractory MM patients. Dr Richardson described the results of cohort 4, which met criteria for expansion as of March 2015.

The investigators enrolled 43 patients in cohort 4 to receive 840 mg daily of ibrutinib plus 40 mg of dexamethasone weekly. This dose of ibrutinib is double the dose approved by the US Food and Drug Administration (FDA) for treatment of CLL and Waldenström’s macroglobulinemia.

The patient population was “very typical” for a relapsed/refractory patient population, Dr Richardson noted. The median age was 65 years (range, 43–81), almost two-thirds were male, and they had a median of 4 (range, 2–10) prior therapies.

More than half of patients had an ECOG performance status of 0 or 1, and their median time since diagnosis was 6.5 years.

Nineteen percent had t(11;14), and other chromosomal abnormalities included del 13q14, t(4:14), and del 17p. Twenty-three patients were ISS stage I, 16 were ISS stage II, and 4 were ISS stage III.

Seventy-seven percent of patients had received an autologous stem cell transplant, 95% had prior alkylator treatment, 91% prior lenalidomide, 58% prior thalidomide, and 91% prior bortezomib treatment.

All patients were steroid-refractory. Thirty-five percent were refractory to alkylator treatment, 61% were refractory to lenalidomide, and 49% were refractory to bortezomib.

“And even a number of them had been exposed to pomalidomide and also to carfilzomib,” Dr Richardson said, “recognizing that these are the new and exciting drugs on the block, but, at the same time, a significant number of our patients already received those therapies.”

Five percent of patients achieved a partial response to ibrutinib and low-dose dexamethasone, and 18% achieved a minimal response, for a clinical benefit rate of 23%. Thirty percent had stable disease after 4 or more cycles.

“What was particularly striking,” Dr Richardson said, “was at the top dose, the 840-mg dose, the progression-free survival.”

The median time to disease progression was 5.4 months (range, 0.0–16.4), which the investigators thought was compelling in this large study.

Dr Richardson noted that there were no significant differences in safety observed across all dose cohorts, although 55% of patients experienced a grade 3 or greater treatment-emergent adverse event (AE), while 29% experienced at least 1 serious AE. And 10% of patients experienced peripheral neuropathy (PN), 8 of whom had a prior history of PN.

Treatment-emergent hematologic AEs of any grade in cohort 4 occurring in more than 20% of patients included anemia (23%) and thrombocytopenia (21%). Grade 3/4 anemia and thrombocytopenia occurred in 9% of patients in each category.

 

 

Treatment-emergent non-hematologic AEs of any grade in cohort 4 occurring in more than 20% of patients included diarrhea (63%), fatigue (49%), cough (26%), nausea (23%), and muscle spasms (21%). Two percent of patients had grade 3/4 diarrhea. There were no other grade 3/4 adverse events in the cohort.

Eighty-six percent of patients in cohort 4 discontinued treatment, 60% due to progressive disease, 12% due to an AE, and 2% at the discretion of the investigator. Twelve percent withdrew, were noncompliant, or required concomitant medication that was not permitted by the protocol.

Overall, Dr Richardson said, the safety profile was manageable, similar across the dosing cohorts, and consistent with those seen in CLL and Waldenström’s macroglobulinemia. The 840-mg dose did not increase toxicity and demonstrated activity in this heavily pretreated population.

“The real signal that struck us,” Dr Richardson emphasized, “was the progression-free survival at 5.4 months . . . for a 92-patient, multicenter experience, this is obviously, I think, an encouraging start.”

Investigators continue to explore ibrutinib in 2 ongoing combination studies, one with carfilzomib and dexamethasone (PCYC-1119) and another with pomalidomide and dexamethasone (PCYC-1138). Another trial with lenalidomide and dexamethasone is planned.

Ibrutinib now has 4 FDA-approved indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.

Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.

Bone marrow aspirate

showing multiple myeloma

NEW YORK—Results of an open-label, phase 2, dose-escalation study of ibrutinib combined with low-dose dexamethasone suggest the Bruton’s tyrosine kinase (BTK) inhibitor may be useful in treating relapsed or relapsed and refractory patients with multiple myeloma (MM).

In the highest dose cohort, 23% of patients experienced a clinical benefit, which was defined as a minimal response or better by International Myeloma Working Group criteria.

“Ibrutinib is a remarkable agent and, through BTK inhibition, has been a game-changer in CLL [chronic lymphocytic leukemia],” said Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Richardson reported results with ibrutinib in MM at Lymphoma & Myeloma 2015.

The rationale for the use of ibrutinib in myeloma is the robust BTK expression in the plasma cells of MM patients as well as its regulation of myeloma “stemness” in the bone marrow.

Ibrutinib plus low-dose dexamethasone has previously demonstrated activity in myeloma at the highest dose tested in a phase 1 trial.

So investigators continued to evaluate ibrutinib in 4 dose cohorts, with and without dexamathesone, and enrolled 92 relapsed/refractory MM patients. Dr Richardson described the results of cohort 4, which met criteria for expansion as of March 2015.

The investigators enrolled 43 patients in cohort 4 to receive 840 mg daily of ibrutinib plus 40 mg of dexamethasone weekly. This dose of ibrutinib is double the dose approved by the US Food and Drug Administration (FDA) for treatment of CLL and Waldenström’s macroglobulinemia.

The patient population was “very typical” for a relapsed/refractory patient population, Dr Richardson noted. The median age was 65 years (range, 43–81), almost two-thirds were male, and they had a median of 4 (range, 2–10) prior therapies.

More than half of patients had an ECOG performance status of 0 or 1, and their median time since diagnosis was 6.5 years.

Nineteen percent had t(11;14), and other chromosomal abnormalities included del 13q14, t(4:14), and del 17p. Twenty-three patients were ISS stage I, 16 were ISS stage II, and 4 were ISS stage III.

Seventy-seven percent of patients had received an autologous stem cell transplant, 95% had prior alkylator treatment, 91% prior lenalidomide, 58% prior thalidomide, and 91% prior bortezomib treatment.

All patients were steroid-refractory. Thirty-five percent were refractory to alkylator treatment, 61% were refractory to lenalidomide, and 49% were refractory to bortezomib.

“And even a number of them had been exposed to pomalidomide and also to carfilzomib,” Dr Richardson said, “recognizing that these are the new and exciting drugs on the block, but, at the same time, a significant number of our patients already received those therapies.”

Five percent of patients achieved a partial response to ibrutinib and low-dose dexamethasone, and 18% achieved a minimal response, for a clinical benefit rate of 23%. Thirty percent had stable disease after 4 or more cycles.

“What was particularly striking,” Dr Richardson said, “was at the top dose, the 840-mg dose, the progression-free survival.”

The median time to disease progression was 5.4 months (range, 0.0–16.4), which the investigators thought was compelling in this large study.

Dr Richardson noted that there were no significant differences in safety observed across all dose cohorts, although 55% of patients experienced a grade 3 or greater treatment-emergent adverse event (AE), while 29% experienced at least 1 serious AE. And 10% of patients experienced peripheral neuropathy (PN), 8 of whom had a prior history of PN.

Treatment-emergent hematologic AEs of any grade in cohort 4 occurring in more than 20% of patients included anemia (23%) and thrombocytopenia (21%). Grade 3/4 anemia and thrombocytopenia occurred in 9% of patients in each category.

 

 

Treatment-emergent non-hematologic AEs of any grade in cohort 4 occurring in more than 20% of patients included diarrhea (63%), fatigue (49%), cough (26%), nausea (23%), and muscle spasms (21%). Two percent of patients had grade 3/4 diarrhea. There were no other grade 3/4 adverse events in the cohort.

Eighty-six percent of patients in cohort 4 discontinued treatment, 60% due to progressive disease, 12% due to an AE, and 2% at the discretion of the investigator. Twelve percent withdrew, were noncompliant, or required concomitant medication that was not permitted by the protocol.

Overall, Dr Richardson said, the safety profile was manageable, similar across the dosing cohorts, and consistent with those seen in CLL and Waldenström’s macroglobulinemia. The 840-mg dose did not increase toxicity and demonstrated activity in this heavily pretreated population.

“The real signal that struck us,” Dr Richardson emphasized, “was the progression-free survival at 5.4 months . . . for a 92-patient, multicenter experience, this is obviously, I think, an encouraging start.”

Investigators continue to explore ibrutinib in 2 ongoing combination studies, one with carfilzomib and dexamethasone (PCYC-1119) and another with pomalidomide and dexamethasone (PCYC-1138). Another trial with lenalidomide and dexamethasone is planned.

Ibrutinib now has 4 FDA-approved indications: patients with CLL who have received at least 1 prior therapy, CLL patients with del 17p, patients with mantle cell lymphoma, and patients with Waldenström’s macroglobulinemia.

Ibrutinib is distributed and marketed as Imbruvica by Pharmacyclics and also marketed by Janssen Biotech, Inc.

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