An unplanned, ad-hoc interim analysis conducted at the request of the US Food and Drug Administration (FDA) showed that the benefit–risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable in patients with relapsed or refractory multiple myeloma. The results from KEYNOTE-183 study are published on 18 July 2019 in The Lancet Haematology.
Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. The KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma.
The KEYNOTE-183 was a randomised, open-label, phase III trial performed at 97 medical centres across 11 countries: Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA. Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy, excluding pomalidomide, and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system.
Patients received oral pomalidomide 4 mg daily on days 1–21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks.
The dual primary endpoints were progression-free survival (PFS) and overall survival (OS).
Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment.
Between January 2016 and June 2017, in total 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (125 patients) or the pomalidomide and dexamethasone group (124 patients).
On 3 July 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study.
Median follow-up was 8.1 months. Median PFS was 5.6 months in the pembrolizumab plus pomalidomide and dexamethasone group versus 8.4 months in the pomalidomide and dexamethasone group. The PFS estimates at 6 months were 48% versus 60% at 6 months (hazard ratio [HR] 1.53; p = 0.98).
Median OS was not reached versus 15.2 months (HR 1.61; p = 0.95); the OS estimates at 6 months were 82% versus 90%.
Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group.
Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group: one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens–Johnson syndrome. Myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.
The study was funded byMerck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
Mateos MV, Blacklock H, Schjesvold F, et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. The Lancet Haematology; Published online on 18 July 2019. pii: S2352-3026(19)30110-3. doi: 10.1016/S2352-3026(19)30110-3.