Ibrutinib Shows Activity in Multiple Myeloma

Heavily pretreated multiple myeloma patients responded to treatment with the oral Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica) plus dexamethasone in a phase 2, open-label, dose-finding trial.

Of the 20 patients treated with the highest dose combination (840 mg daily ibrutinib with 40 mg of dexamethasone weekly in cohort 4), five (25%) had a response of minimal or better; one patient had a partial response. The median follow up was 15.2 months. These results were presented  at the 2014 American Society of Hematology annual meeting by Ravi Vij, MD, of Washington University in St. Louis.

Clinical activity was seen in all of the dosing cohorts, with increasing activity as the dose of drug increased.

An additional five patients had stable disease for four or more cycles in three other cohorts, including two ibrutinib monotherapy groups. In the lower, 420 mg ibrutinib monotherapy cohort, there was one partial response and one minimal response as well as two patients with stable disease for four cycles or more. An additional 10 patients had stable disease for four or more cycles in two cohorts. Several of the responses were longer lasting, including one patient in the 420 mg ibrutinib monotherapy cohort who has had an ongoing response lasting for 2 years.

The median progression-free survival in cohort 4 was 5.6 months, and ranged between 1.0 and 4.3 months in the other three cohorts.

Additional patients have since enrolled onto the highest combination dose cohort of the trial. According to the study abstract, additional patient analyses--including changes in cytokines and bone metabolism--are being measured.

Ibrutinib was approved by the Food and Drug Administration (FDA) for patients with chronic lymphocytic leukemia (CLL), a type of non-Hodgkin lymphoma, including those with a chromosome 17 deletion (17p deletion) that is associated with poor responses to standard of care therapies. The drug targets BTK, an enzyme necessary for the development of fully functional B-cells. The enzyme is known to be upregulated in malignant B-cells. Malignant myeloma cells have increased BTK expression compared to non-malignant cells. Blocking BTK activity in myeloma has been shown to inhibit growth of tumors and release of osteoclast-derived tumor growth factors. These and other preclinical data provided the impetus for the phase 2 trial.

Patients on the trial had a median age of 64 and one-fifth had either a del17p or a p53 deletion. The median prior number of therapies was four and ranged from two to 14; 41% of patients had five or more prior therapies. Eighty-percent of patients had had an autologous stem cell transplant and the majority (62%) had been refractory to their prior therapy--including an immunomodulatory drug and a proteasome inhibitor.

Patients in all four dosing cohorts had similar adverse events and the safety profile overall was tolerable, according to Vij. The most common non-hematologic adverse events--most of which were Grade 1 or 2--were diarrhea (51%), fatigue (41%), nausea (35%), dizziness (25%), and muscle spasms (23%).  Fifty-seven percent of patients had an adverse event of Grade 3 or higher and 22% of patients required a dose modification due to an adverse event. Six patients discontinued due to an adverse event.

Hematologic adverse events of Grade 3 were anemia (16%), thrombocytopenia (9%), and neutropenia (4%).

Ibrutinib is currently being evaluated in combination with carfilzomib in an ongoing Phase1/2b study.