September-October 2017, Volume 14, Issue 5
Combining PD-1 Inhibition With Pemalidomide for Relapsed/Refractory Multiple Myeloma
Published on: August 14, 2017
Badros A, Hyjek E, Ma N, et al. Pembrolizumab, pomalidomide and low dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;pii:blood-2017-03-775122. [Epub ahead of print].
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%).
Monoclonal antibody therapies targeting the PD-1 receptor look promising in MM when used in combination with approved therapies such as pomalidomide. The data from this trial demonstrate an excellent response rate in a heavily pretreated MM population with expected and tolerable toxicity. That said, ongoing studies of pembrolizumab and this combination in MM are currently on hold. KEYNOTE-183 (clinicaltrials.gov Identifier, NCT02576977), the phase III, randomized, registration study of pembrolizumab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone alone, and KEYNOTE-185 (NCT02579863), the phase III study comparing lenalidomide and low-dose dexamethasone with pembrolizumab to lenalidomide and low-dose dexamethasone alone in patients with newly diagnosed and treatment-naïve MM who are ineligible for autologous stem cell transplant, were recently placed on hold for further investigation of an increased number of deaths in the pembrolizumab containing arms. Checkpoint inhibition is an area of great interest within oncology and holds promise in MM, but awaits further clarification regarding its safety in this patient population.
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Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34:2698-2704.
Görgün G, Calabrese E, Soydan E, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood. 2010;116:3227-3237.
San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-1066.
Conflict of Interests
Dr. Raje and Dr. O'Donnell indicated no relevant conflicts of interest.
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