Pembrolizumab combined with lenalidomide and low‐dose dexamethasone for relapsed or refractory multiple myeloma: phase I KEYNOTE‐023 study

Multiple myeloma (MM) is characterised by generalised immune suppression, partly mediated by loss of T-cell repertoire, inhibition of antigen-presenting cells and increased expression of the inhibitory programmed death 1 (PD-1, also termed PDCD1) immune checkpoint pathway, (Neri et al, 2016). PD-1 up-regulation on T cells is associated with disease relapse and resistance to chemotherapy (Tamura et al, 2013), and blockade may represent a promising treatment option. However, single-agent PD-1 inhibition did not show significant tumour regression, suggesting that combination therapy may be necessary (Lesokhin et al, 2016). In pre-clinical studies, lenalidomide, an immunomodulatory drug (IMiD), plus PD-1/PD-L1 (CD274) blockade enhanced MM cell death induced by PD-1/PD-L1 immune checkpoint blockade alone (Gorgun et al, 2015). The KEYNOTE-023 study (NCT02036502), an open-label, phase I, multi-centre, multi-cohort dose-finding study, evaluated efficacy and safety of the PD-1 inhibitor, pembrolizumab, in combination with lenalidomide and low-dose dexamethasone in patients with relapsing/remitting MM (RRMM). Enrolled patients had confirmed diagnosis of MM and were previously treated with at least two lines of antimyeloma therapy. Primary endpoints were safety and determination of the maximum tolerated dose (MTD) or maximum administered dose of pembrolizumab plus lenalidomide and low-dose dexamethasone. Secondary endpoints included objective response rate (ORR) and disease control rate (DCR) by investigator assessment per International Myeloma Working Group (IMWG) 2006 criteria (Durie et al, 2006). Exploratory objectives included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Safety was analysed in all patients who received at least one dose of study treatment (ASAT population). Efficacy endpoints, excluding OS, were analysed in the response-evaluable (RE) population of all treated patients with at least two available post-baseline efficacy assessments. (Additional methods, provided in Tables SI–SIII). In the dose-determination stage, six patients received 2 mg/kg pembrolizumab, 25 mg lenalidomide and 40 mg dexamethasone (Fig S1). Of these, three patients experienced dose-limiting toxicity (DLT) and recovered without treatment discontinuation. Subsequently, the lenalidomide dose was de-escalated to 10 mg for the other three patients in the dose-determination stage, none of whom experienced DLT. The preliminary MTD was 2 mg/kg pembrolizumab, 10 mg lenalidomide and 40 mg dexamethasone. Patients in all subsequent stages were treated with a 200-mg fixed dose of pembrolizumab instead of 2 mg/kg, based on similar pharmacokinetics (Ahamadi et al, 2016). In the dose-confirmation phase, the lenalidomide dose was increased to 25 mg, with no additional toxicity observed. Therefore, 200 mg pembrolizumab every 2 weeks, plus 25 mg lenalidomide on days 1–21, and 40 mg dexamethasone orally weekly during each 28-day cycle was confirmed as the final MTD and used in the dose-expansion phase. Sixty-six patients were enrolled; 62 were treated (ASAT population). Forty-seven (75 8%) discontinued the study, mostly because of progressive disease (n = 34, 54 8%) (Fig S2). Twelve were not evaluable for efficacy and were excluded from the RE population (protocol violations [n = 1], missing baseline [n = 1] or post-baseline [n = 10] disease assessments). At database cut-off (10 March 2017), median follow-up was 18 9 months (range, 0 8–36 0 months). Median age was 61 years; patients were heavily pre-treated (Table SIV). Patients received a median (range) of 7 0 (1–67) cycles of pembrolizumab. All 62 patients experienced adverse events (AEs; Table SV). Two (3 2%) patients died of AEs—veno-occlusive liver disease (unrelated to study treatment) and ischaemic stroke (related to lenalidomide) (Supporting Information Results). Fifty-nine (95 2%) patients experienced treatment-related adverse events (TRAEs), most commonly (≥20%), thrombocytopenia (37 1%), neutropenia (32 3%), anaemia (25 8%), diarrhoea and fatigue (22 6%, each) (Table I). Thirty-seven (59 7%) experienced grade 3–5 TRAEs (Table I). Two (3 2%) discontinued treatment because of TRAEs (ischaemic colitis and ischaemic stroke). Twenty-five (40 3%) experienced treatment interruption because of TRAEs (Table SVI). Immune-mediated AEs occurred in eight (12 9%) patients. None were fatal or necessitated treatment discontinuation. ORR was 44 0% and DCR was 94% (Table II); response was similar in lenalidomide-refractory patients (Table SVII). Additional efficacy outcomes are presented in the Supporting Information Results (Figs S3–S5). Responses were durable in the overall study population, with a median DOR of 18 7 months. Median PFS and OS were 7 2 months and not reached (NR), respectively. These findings are consistent with correspondence