Jesus San Miguel, MD, PhD
The addition of the PD-1 inhibitor pembrolizumab (Keytruda) to an established multiple myeloma regimen elicited responses in 76% of 17 patients with relapsed/refractory disease in findings from one of several clinical trials presented at the 2015 ASH Annual Meeting that provide early signals that the immunotherapy agent may have an impact on hematologic malignancies.
In the KEYNOTE-023 trial,1
patients with multiple myeloma who were treated with pembrolizumab, lenalidomide, and low-dose dexamethasone derived clinical benefit from the combination without experiencing excessive toxicities.
Among the 13 patients who responded to the combination therapy, 4 patients (24%) achieved a very good partial response and 9 patients (53%) exhibited a partial response. Additionally, 3 patients (18%) had stable disease, leaving only 1 patient whose disease progressed. The disease control rate, which measured any response plus stable disease lasting >12 weeks, was 88%.
Results were similarly strong among the 9 patients who were refractory to lenalidomide. Five of these patients were among the responders, including 2 participants with a very good partial response and 3 with a partial response.
At a median follow-up of 296 days, the median duration of response was 9.7 months and the median time to achieve the first objective response was 1.2 months (range, 1.0-6.5 months).
“Initial efficacy results show promising activity in heavily pretreated patients with relapsed/refractory multiple myeloma and support the continued development of pembrolizumab in patients with multiple myeloma,” said Jesus San Miguel, MD, PhD, of Clínica Universidad de Navarra in Pamplona, Spain, who presented the findings during an oral session.
Pembrolizumab, which the FDA has approved in melanoma and non–small cell lung cancer, is being explored extensively in multiple myeloma and other hematologic malignancies, according to Merck, the company developing the drug.
In October, Merck launched the phase III KEYNOTE-185 trial,2
which calls for randomizing an estimated 640 patients with newly diagnosed, treatment-naïve multiple myeloma who are not eligible for a stem cell transplant either to a regimen similar to that used in the KEYNOTE-023 trial or to lenalidomide/dexamethasone alone.
In addition, pembrolizumab is being evaluated in patients in separate clinical trials in classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma.
“PD-1 blockade, through checkpoint inhibitors to unleash the immune system, has generated tremendous enthusiasm over the last few years in a number of cancers. This therapy, already approved in lung cancer, has also shown very promising results in highly refractory blood cancers,” Andre Goy, MD, chairman of John Theurer Cancer Center (JTCC) and chief of the Division of Lymphoma at Hackensack University Medical Center in New Jersey, said in a statement.
JTCC researchers served as coauthors of the abstracts for the KEYNOTE-023 trial and for the phase I KEYNOTE-013 trial3
in patients with cHL.
Key Multiple Myeloma Findings
In multiple myeloma, San Miguel said scientific and preclinical studies have established a rationale not only for targeting PD-1, but also for combining a PD-1 inhibitor with an immunomodulatory agent, such as lenalidomide. He said that PD-L1 is expressed on the clonal tumor cell across all stages of multiple myeloma, but that levels are particularly high on the T cells of patients who are minimal residual disease positive.
“Lenalidomide reduces PD-L1 and PD-1 expression on multiple myeloma cells, and on T cells and myeloid-derived suppressor cells,” San Miguel said. “Lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against multiple myeloma cells.”
Meanwhile, pembrolizumab, a humanized monoclonal antibody of the IgG4/kappa isotype, directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
The 2 agents function synergistically when used together, San Miguel said. “Lenalidomide will increase the number of T cells and the T-cell activation, and anti-PD-1 [agent] will release the brake” so that the activated T-cells attack the tumor, he said.
In the KEYNOTE-023 study, researchers were seeking to determine the maximum tolerated dose (MTD) for the combination. Safety and tolerability were the primary endpoints of the study, while secondary endpoints included overall response rate, duration of response, progression-free survival, and overall survival.
After testing several doses, San Miguel said researchers established the MTD as a 200 mg fixed dose of pembrolizumab administered intravenously twice a month without premedication along with 25 mg of lenalidomide on days 1 to 21 of the cycle and 40 mg of dexamethasone weekly.