Combining PD-1 Inhibition With Pemalidomide for Relapsed/Refractory Multiple Myeloma

Dr. Ashraf Badros and colleagues report the results of the phase II study of pembrolizumab, pomalidomide, and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2 have emerged as potential targets for a number of different cancers. Blockade of this pathway has led to durable remissions in patients with a variety of different malignancies including advanced melanoma, non–small-cell lung cancer, renal cell carcinoma, and now, hematologic malignancies.¹  PD-L1 is overexpressed on MM cells, particularly in the RR setting.²  PD-L1 expression has been shown to induce drug resistance in MM cell lines through the PI3K/Akt signaling pathway,³  and although this would therefore appear to be a desirable target for MM, there was a lack of objective responses to the anti–PD-1 antibody, nivolumab, when tested as a single agent in MM.⁴  The results suggest a need for an immune-stimulatory strategy in combination with PD-1/PD-L1 blockade to restore effector T cell function in RRMM. Pomalidomide is an immunomodulatory drug (IMiD). As a class, the IMiDs augment the immunologic bone marrow miroenvironment in multiple ways, including stimulating effector cytotoxic T lymphocytes, inhibiting regulatory T cells, and altering a broad range of cytokines.⁵  Combining PD-1/PD-L1 blockade with IMiDs is a logical approach to enhancing the efficacy of targeting this pathway. Pembrolizumab is a humanized monoclonal IgG4 antibody targeting the PD-1 receptor. In this study, pembrolizumab was combined with pomalidomide and low-dose dexamethasone for the treatment of RRMM based on this rationale.

Eligible patients had to have received at least two lines of prior therapy, including a proteasome inhibitor (PI) and an IMiD. Prior pomalidomide was allowed if the patient had had a response and had been off therapy for six months. Forty-eight patients were enrolled. The median number of prior lines of therapy was three (range, 2-5), 35 patients (73%) were refractory to both PIs and IMiDs, and 30 patients (62%) had high-risk cytogenetics. Patients were treated with 200 mg of pembrolizumab intravenously every two weeks, pomalidomide 4 mg daily for 21 days, and dexamethasone 40 mg weekly on a 28-day cycle.

Objective response rate (ORR) was a primary endpoint of the study. The ORR was 60 percent including four (8%) stringent complete responses, nine (19%) very good partial responses, and 16 (33%) partial responses. This compares favorably with the historical control of pomalidomide and dexmaethasone alone, which had an ORR of 31 percent.⁶  At median follow-up of 15.6 months (95% CI, 9.2-17.5), progression-free survival was 17.4 months (95% CI, 11.7-18.8), and overall survival was not reached (95% CI, 18.9-NR).

In terms of safety and tolerability, the pembrolizumab combination was relatively well tolerated. Grade 3 to 4 adverse events occurred in 19 (40%) of the patients and included hematologic toxicities in 19 (40%), hyperglycemia in 12 (25%), and pneumonia in seven (25%) of these individuals. Autoimmune events were limited, were mostly grade 2 or less, and included pneumonitis in six patients (13%) and hypothyroidism in five patients (10%).