Pembrolizumab in combination with lenalidomide and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM): randomized, phase 3 KEYNOTE-185 study

Abstract

Background: PD‐L1 is expressed on MM plasma cells and has been associated with higher MM cell proliferation. Thus, PD‐L1 blockade with pembrolizumab may act synergistically with immunomodulatory drugs to enhance MM tumor suppression. In the phase 1 KEYNOTE‐023 study, pembrolizumab + lenalidomide and low‐dose dexamethasone showed an acceptable safety profile and promising preliminary efficacy in patients with relapsed/refractory MM, supporting further evaluation of this treatment combination. The randomized, open‐label, phase 3 KEYNOTE‐185 study (ClinicalTrials.gov, NCT02579863) was designed to compare the efficacy and safety of lenalidomide and low‐dose dexamethasone (standard of care) with or without pembrolizumab in patients with newly diagnosed and treatment‐naive MM. Trial design: Key eligibility criteria include age ≥18 years, newly diagnosed, treatment‐naive, active MM with measurable disease, and ineligibility for autologous stem cell transplantation. Patients will be randomized 1:1 to receive lenalidomide 25 mg daily on days 1‐21 and low‐dose dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28‐day cycles, with or without pembrolizumab 200 mg every 3 weeks. Patients will be stratified based on age (<75 vs ≥75 years old) and International Staging System stage (ISS I or II vs ISS III). Treatment will continue until disease progression or unacceptable toxicity. Response will be assessed every 28 days by Clinical Adjudication Committee blinded central review and by investigator review based on International MyelomaWorking Group (IMWG) 2011 response criteria. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for events of clinical interest) and graded per NCI CTCAE v4.0. The primary end point is progression‐free survival (PFS) as assessed by central review according to IMWG criteria; secondary end points are overall survival, overall response rate, duration of response, second PFS, and safety and tolerability. KEYNOTE‐185 will enroll ∼640 patients from multiple sites.