Checking Multiple Myeloma with Pembrolizumab

A Phase III Study of Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK3475) in Refractory or Relapsed and Refractory Multiple Myeloma (Keynote 183); A Phase III Study of Lenalidomide and Low-dose Dexamethasone With or Without Pembrolizumab (MK3475) in Newly Diagnosed and Treatment Naïve Multiple Myeloma (Keynote 185)

NCT02576977 (in relapsed patients); NCT02579863 (in newly diagnosed patients)

Merck Sharpe & Dohme Corp.

33 and more centers in the United States and worldwide (in relapsed patients); 39 and more centers in the United States and worldwide (in newly diagnosed patients)

300 patients (in relapsed patients); 640 patients (in newly diagnosed patients)

Both of these trials are phase III randomized studies to evaluate the efficacy or progression-free survival of combining the anti-PD1 monoclonal antibody pembrolizumab with standard immunomodulatory therapy in multiple myeloma (MM) in patients with relapsed/refractory or newly diagnosed disease. In the former study, patients who have had two or more prior lines of treatment and who have been previously exposed to an immunomodulatory drug and a proteasome inhibitor are eligible; these criteria are similar to the U.S. Food and Drug Administration indication for pomalidomide. In the latter study, newly diagnosed patients who are not eligible for autologous stem cell transplantation are eligible. In both studies, pembrolizumab is given 200 mg intravenously every three weeks, with the conventional 28-day immunomodulatory drug schedule: pomalidomide 4 mg by mouth on days 1 to 21 with low-dose dexamethasone (40 mg weekly) in relapsed/refractory patients, or lenalidomide 25 mg by mouth on days 1 to 21 with low-dose dexamethasone.

In cancer initiation and development, tumor cells suppress immune surveillance by using PD-L1 ligand to engage the PD1 receptor on T cells and inhibit T cell activation.¹  Checkpoint inhibitors targeting PD1 therefore restore T cell activity against tumor cells and have emerged as a vital new therapeutic strategy. Two anti-PD1 antibodies, nivolumab and pembrolizumab, are now approved in melanoma and lung cancer. The promise of anti-PD1 antibodies is starting to be explored in hematologic malignancies such as Hodgkin disease.² 

In MM, myeloma cells have increased levels of PD-L1, and the immunomodulatory drugs lenalidomide and pomalidomide inhibit myeloid-derived suppressor cell–mediated immune suppression in vitro.³  Furthermore, immunomodulatory drugs activate natural killer cells,⁴  and they may augment anti-PD1 antibody enhancement of natural killer cell function against MM.⁵  As a single agent, nivolumab had minimal activity in relapsed MM, with a stable disease rate of 67 percent in a phase I trial; partial responses or better were not seen.⁶  However, in combination, two studies presented at the 57th ASH Annual Meeting showed promising results for pembrolizumab with lenalidomide⁷  or pomalidomide,⁸  both with dexamethasone, in relapsed myeloma. The former trial with lenalidomide demonstrated an ORR of 74 percent in patients with two or more prior lines of treatment. In the latter trial with pomalidomide, the ORR was 50 percent, and these patients were heavily pre-treated, with a median of three prior lines of treatment, and 75 percent were refractory to both immunomodulatory drugs and proteasome inhibitors. In both studies, the treatments were tolerated well, and there were no treatment discontinuations for adverse events.

Checkpoint inhibition is emerging as an important new tool in cancer treatment. Its efficacy was first seen in solid tumors such as melanoma and lung cancer, and preclinical work as well as early-stage clinical trials with pembrolizumab in combination with lenalidomide or pomalidomide show auspicious findings for MM. The ongoing randomized studies of pembrolizumab in relapsed and newly diagnosed disease are important studies for validating this type of immuno-oncology as a novel therapeutic platform in MM.