Ibrutinib is a first-in-class oral Bruton’s tyrosine kinase (BTK) inhibitor that has shown promising clinical activity as a single agent or in combination with dexamethasone in heavily pretreated patients with relapsed or relapsed/refractory multiple myeloma (RRMM).1 Preclinical evidence indicates BTK inhibition may overcome resistance to proteasome inhibitors (PIs), and that it has synergistic activity with PIs.2,3 Chari and colleagues reported preliminary results of an ongoing phase 1/2b study (PCYC-1119) of ibrutinib plus carfilzomib ± dexamethasone in patients with RRMM who had received ?2 prior therapies, including bortezomib and an immunomodulatory drug (IMiD).4 In the phase 1 portion, 40 patients were treated with ibrutinib plus carfilzomib ± dexamethasone across multiple dose levels. Patients in cohort 1 (n=3) received ibrutinib 560 mg daily plus carfilzomib20/27 mg/m2 twice daily; cohort 2a received ibrutinib 560 mg daily plus carfilzomib20/36 mg/m2 twice daily (or plus dexamethasone 20 mg twice weekly in cohort 2b); cohort 3b received ibrutinib 840 mg daily plus carfilzomib20/36 mg/m2 twice daily plus dexamethasone 20 mg twice weekly. No dose-limiting toxicities were observed, and cohorts 2b and 3b were chosen for dose expansion. Overall, patients had received a median of 3 prior lines of therapy; all had received prior bortezomib, lenalidomide and corticosteroids, 88% were refractory to their last therapy, 73% refractory to bortezomib, 73% refractory to lenalidomide, and 58% refractory to both IMiDs and PIs. Overall, among the 39 patients evaluable for efficacy, an objective response rate (ORR) of 62% and a clinical benefit rate (CBR) of 72% were achieved. In cohort 3b, the ORR and CBR were 65% and 76%, respectively, and in cohort 2b, the ORR was 64% and CBR was 79%. Responses were also achieved in 7 of 10 patients with t(4:14) and/or del 17p cytogenetic abnormalities. In terms of safety, 11 patients reported treatment-related serious adverse events (AEs). Grade 3/4 hematologic AEs included thrombocytopenia (18%) and anemia (18%); grade 3/4 non-hematologic AEs included pneumonia (18%), hypertension (20%), diarrhea (13%), fatigue (13%) and acute renal events (8%). A total of 29patients discontinued study treatment, 12 due to progressive disease, 8 due to an AE, and 5 due to investigator decision, and 4 due to patient withdrawal. Patients remained on study for a median of 11 months. Based on these results, the cohort 3b dose (ibrutinib 840 mg daily plus carfilzomib20/36 mg/m2 twice daily plus dexamethasone 20 mg twice weekly) was determined to be the recommended phase 2 dose. These preliminary results indicate promising clinical activity for an ibrutinib plus carfilzomib combination in a heavily pretreated refractory difficult-to-treat patient population, with no new safety signals or exacerbation of known toxicities.
