Efficacy and safety of ibrutinib in RRMM

The addition of novel agents in the treatment regimens for relapsed and refractory multiple myeloma (RRMM) patients has led to a significant improvement in patient outcomes. However, due to the high rate of relapse in MM there is still a need to investigate the use of new agents. The B-cell receptor-signaling pathway shows promise as a new therapeutic target in MM. Ibrutinib, an orally administered inhibitor of Bruton’s tyrosine kinase (BTK), is used for the treatment of patients with mantle cell lymphoma.

To assess the efficacy and safety of ibrutinib in MM, Paul G. Richardson, from the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, US, and colleagues, conducted a phase II study (PCYC-1111; NCT01478581) with incremental dosing of ibrutinib, both as a monotherapy and in combination with dexamethasone (dex) in RRMM patients (≥2 lines of therapy, including Proteasome Inhibitors (PI) or Immunomodulatory drugs (IMiD)). The primary endpoint of the study was clinical benefit rate (CBR) and the findings were published in the British Journal of Haematology in February 2018.

Study Design:

• The study included four cohorts:
  • Cohorts 1 & 3: ibrutinib monotherapy (420 and 840 mg/day, respectively) with 40 mg of dex allowed on disease progression (once weekly)
  • Cohorts 2 & 4: ibrutinib (560 and 840 mg/day, respectively) in combination with 40 mg of oral dex (once weekly)

Demographics:

• N = 92 patients (pts) with RRMM; Median age = 62–66 years
• All patients (pts) had received prior steroid treatment
• Median number of prior regimens (range) = 3.5 (2–14); median follow-up = 23 months

Table 1. Patient characteristics.

Key findings:

• Highest overall response observed in cohort 4: CBR = 28%
• Median duration (range) = 9.2 (3.0–14.7) months

Table 2. Overall response for each cohort according to the International Myeloma Working Group (IMWG) criteria.

Abbreviations used: PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease; ORR, overall response rate; PFS, progression-free survival

Safety:

• Median duration of ibrutinib (months): cohort 1 = 3.9; cohort 2 = 2.6; cohort 3 = 4.0; cohort 4 = 4.5
• No clinically significant differences in safety observed across cohorts
• Most frequent adverse events (AEs) across all cohorts: diarrhea (53%), fatigue (43%), nausea (30%), anemia (28%), thrombocytopenia (25%), muscle spasms (24%), cough (23%), insomnia (21%), upper respiratory tract infection (21%), arthralgia (20%), rash = 11 pts
• Grade 3 AEs: Non-hematological = pneumonia (7%); Hematological = anemia (16%), thrombocytopenia (11%), and neutropenia (2%)
  • Atrial fibrillation = 1 pt
  • Acute kidney injury = 1 pt
• Treatment discontinuation due to renal impairment = 2 pts

The highest activity of ibrutinib was observed in cohort 4, in which patients were given the highest dose (840 mg/ day), along with low-dose dex on a weekly basis; increasing doses of dex also correlated with a longer PFS. The addition of dex clearly enhanced the efficacy of ibrutinib, with an increase in median PFS in comparison to ibrutinib alone. Future studies are likely to build on this dosing trial to assess ibrutinib in combination with other novel agents.