Inhibition of immune checkpoint proteins such as programmed death-1 (PD-1) has emerged as an effective therapeutic strategy in several cancer types. Current evidence indicates that overexpression of programmed death ligand 1 (PD-L1) is associated with tumor invasiveness in multiple myeloma (MM), and its inhibition with pembrolizumab, a humanized anti–PD-1 monoclonal antibody that directly blocks the interaction between PD-1 and PD-L1, coupled with immunomodulatory drugs (IMiDs) increases tumor suppression.1-3 KEYNOTE-023 is an open-label, phase 1, dose-escalation trial that evaluated the safety, tolerability, and efficacy of pembrolizumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory MM (RRMM) who have failed ?2 prior therapies, including a proteasome inhibitor and an IMiD. San Miguel and colleagues presented preliminary data of the dose determination and confirmation, safety and tolerability data, and preliminary efficacy data.4 In this trial, a modified 3+3 design was used for dose determination followed by dose confirmation and expansion arms. During the dose determination phase, 3 to 6 patients were enrolled in each cohort and treated with pembrolizumab (2 mg/kg, every 2 weeks) plus lenalidomide (10 mg or 25 mg, days 1-21) and low-dose dexamethasone (40 mg weekly). After identification of maximum tolerated dose (MTD), patients in the dose confirmation and expansion arms were treated at a fixed dose of 200 mg of pembrolizumab plus lenalidomide 25 mg and dexamethasone 40 mg. A total of 17 patients with RRMM were enrolled in the dose determination and confirmation arms of the study; 6 patients were treated with pembrolizumab 2 mg/kg and lenalidomide 25 mg, and 11 patients with pembrolizumab 2 mg/kg or a fixed dose of 200 mg and lenalidomide 10 mg or 25 mg. The dose expansion arm of the study enrolled 33 patients who were treated with pembrolizumab 200 mg, lenalidomide 25 mg, and dexamethasone 40 mg. Overall, 72% of patients had ?3 prior therapies, 76% were refractory to lenalidomide, 64% were refractory to bortezomib, and 50% had double-, triple-, or quadruple-refractory disease. Treatment-related adverse events (AEs) of any grade were experienced by 36 (72%) patients; 23 (46%) patients experienced grade 3/4 treatment-related AEs. No deaths or treatment discontinuations for toxicity were reported. The most frequent treatment-related AEs were thrombocytopenia (28%), neutropenia (24%), fatigue (14%), and anemia, hyperglycemia, and muscle spasms (10% each). Dose-limiting toxicities were reported by 3 patients in the 25-mg lenalidomide cohort, including grade 3/4 neutropenia, grade 3 infectious pneumonia, and grade 3 tumor lysis syndrome with grade 4 hyperuricemia; all patients recovered without treatment discontinuation. Therefore, the MTD was defined as pembrolizumab 200 mg fixed dose in combination with lenalidomide 25 mg and low-dose dexamethasone 40 mg. Immune-mediated AEs (all grade 1 or 2) were observed in 2% to 4% of patients and included adrenal insufficiency, hyperthyroidism, hypothyroidism, and thyroiditis. At a median follow-up of 287 days in 17 evaluable patients, the overall response rate (ORR) was 76%, including 24% who achieved a very good partial response (VGPR) and 53% who achieved a partial response (PR). Patients with IMiD-refractory and double-refractory disease achieved an ORR of 56%, VGPR of 22%, and PR of 33%. These early results of the KEYNOTE-023 trial indicate that immunotherapy with pembrolizumab plus lenalidomide/dexamethasone is a promising antimyeloma strategy in heavily pretreated patients with RRMM.
