Ibrutinib is an essential enzyme in the B-cell receptor signaling pathway. Although BTK is essential for the development and function of B-cells and is downregulated in plasma cells, the expression of BTK in malignant plasma cells is increased 4-fold and is comparable with BTK expression levels in CLL and MCL. In addition, preclinical models show that BTK inhibition with ibrutinib led to the direct inhibition of osteoclast bone resorption and the release of osteoclast-derived tumor growth factors, suggesting that ibrutinib may have a role in the treatment of multiple myeloma (MM; Tai YT, et al. Blood. 2012;120:1877-1887). Thus, Vij and colleagues reported on an open-label phase 2 dose escalation study to evaluate the efficacy, safety, and pharmacokinetics of ibrutinib in patients with relapsed/refractory MM who had documented nonresponsive/progressive disease after at least 2 previous lines of therapy, including at least 1 immunomodulatory agent (Vij R, et al. ASH 2014. Abstract 31).
A total of 69 patients were treated in 1 of 4 cohorts (cohort 1, ibrutinib 420 mg daily; cohort 2, ibrutinib 560 mg daily plus dexamethasone 40 mg weekly; cohort 3, ibrutinib 840 mg daily; cohort 4, ibrutinib 840 mg daily plus dexamethasone 40 mg weekly), with a median follow-up of 15.2 months; 20% of the patients had either a deletion in chromosome 17p or a p53deletion. The median number of previous therapies was 4 (range, 2-14), 41% had ?5 previous therapies, and 80% of patients had undergone autologous stem-cell transplant.
The highest activity with a clinical benefit rate of 25%—including 1 partial remission (PR), 4 minor responses (MRs), and 5 sustained (>4 cycles) stable disease—was observed in cohort 4, which led to the expansion of this cohort per the protocol design. Overall, 57% of the patients experienced a grade ?3 adverse event, including diarrhea (51%), fatigue (41%), nausea (35%), dizziness (25%), and muscle spasms (23%). Myelosuppression had a reported overall incidence of any-grade anemia (29%), thrombocytopenia (23%), and neutropenia (7%), with 16%, 9%, and 4% being grade 3, respectively. There were no clinically meaningful differences among the dose levels.
At the time of the data cut-off, 7 patients remain on the study treatment. The most common reason for treatment discontinuation was progressive disease in 47% of patients, with additional patients discontinuing as a result of investigator discretion (18%), patient decision (7%), and noncompliance (3%). These data suggest that in this heavily pretreated patient population, ibrutinib, as a single agent and in combination with dexamethasone, demonstrated evidence of antitumor activity. There was a trend toward improved efficacy (MR or better) in cohort 4, and treatment was well-tolerated with manageable toxicities.
Ongoing correlative studies are being conducted to determine changes in cytokines, chemokines, and indices of bone metabolism, and to determine the effect of dexamethasone on the pharmacokinetic profile of ibrutinib. In addition, ibrutinib is currently being evaluated in combination with carfilzomib in an ongoing phase 1/2b study.
