Saad Z. Usmani, MD
Checkpoint inhibition may have demonstrated promising findings in some hematologic malignancies, such as Hodgkin lymphoma, but PD-1/PD-L1 inhibitors have caused safety concerns when added to immunomodulatory agents in others, specifically multiple myeloma.
In Hodgkin lymphoma, the FDA approved nivolumab (Opdivo) in March 2016 for the treatment of patients with classical disease that has relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin (Adcetris). The decision marked the first PD-1 inhibitor approved for a hematologic malignancy.
Meanwhile, in multiple myeloma, the FDA in September 2017 placed partial clinical holds on 3 trials—the phase III CheckMate-602, phase I CheckMate-039, and phase II CA204142 studies—assessing nivolumab-based combinations in patients with relapsed/refractory disease. These were based on safety concerns previously reported in 2 pembrolizumab (Keytruda)-based studies in myeloma, KEYNOTE-183 and KEYNOTE-185, which led to the FDA placing clinical holds on them in July 2017.
However, in December 2017, clinical holds on 2 of the nivolumab trials, CheckMate-039 and CA204142, were lifted.
While the role of immunotherapy has not yet been determined in multiple myeloma, Saad Z. Usmani, MD, explained that other combination strategies with checkpoint blockade are being explored across the hematologic malignancy field.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Hematologic Malignancies, Usmani, director of clinical research (hematologic malignancies), director of plasma cell disorders, clinical associate professor of medicine, University of North Carolina at Chapel Hill, Levine Cancer Institute, Atrium Health, discussed the current state of immune checkpoint inhibitors in hematologic cancers, recent setbacks, and ongoing studies that could further shape the landscape.
OncLive: You lectured on immunotherapy for B-cell malignancies and multiple myeloma. What did you share with the audience?
My presentation covered some of the emerging and future immunotherapy strategies for B-cell malignancies, as well as multiple myeloma. These would include not just the monoclonal antibody-based strategies, but also cellular therapy–based strategies, including T-cell receptor (TCR) T cells, CAR T cells, and bispecific monoclonal antibodies. [I also provided] some of the historic perspective efficacy data, as well as safety profile issues, and where we are heading in the field with regards to those technologies.
Earlier studies have showed minimal efficacy with checkpoint inhibitors in B-cell malignancies and even less in multiple myeloma. Can you speak to how efforts have evolved since then?
In terms of the PD-1/PD-L1 pathway, we have seen efficacy first in the Hodgkin lymphoma realm; the original clinical observations were published a little more than 3 years ago in the New England Journal of Medicine
, and that was with nivolumab in advanced patients with Hodgkin lymphoma.
Since then, several clinical trials have explored early relapse, frontline strategies, and the posttransplantation realm. It looks like, in each of those strategies, there is good activity utilizing PD-1 and PD-L1 inhibitors.
In myeloma, we only have clinical data with pembrolizumab in combination with lenalidomide (Revlimid)/dexamethasone as well as pomalidomide (Pomalyst)/dexamethasone. These data were generated in small single-center phase I/II trials. The phase III trials were held by the FDA in the summer of 2017. Subsequently, checkpoint inhibition was deemed not safe with immunomodulatory drugs. However, newer clinical trials combining checkpoint inhibitors with other drug classes in myeloma are ongoing.