Hearn Jay Cho, MD, PhD
In 2017, the FDA halted trials examining checkpoint inhibitors in multiple myeloma due to excess toxicity, which left an unclear role for this class of agents in this disease.
Now, there are 3 classes of immunotherapy under investigation in myeloma: checkpoint inhibitors, antibody-drug conjugates (ADCs), and bispecific T-cell engagers (BiTEs), said Hearn Jay Cho, MD, PhD. He added that the mechanism of action of these drugs and optimal combinations need to be better understood to improve outcomes.
“If we understand the mechanisms of these agents, we could understand how to logically combine them. To make real, rationale combinations of immune therapies, we have to know what they're doing. That's the knowledge deficit that needs to be filled right now,” said Cho.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Multiple Myeloma, which was held ahead of the 2018 ASH Annual Meeting, Cho, associate professor of Medicine, Hematology/Oncology, Mount Sinai Hospital, discussed these classes of immunotherapy under investigation in multiple myeloma.
OncLive: What types of immunotherapy are being investigated?
: I covered 3 classes of immunotherapies. The first class is checkpoint inhibitors. These have already been approved for patients with solid tumors and classical Hodgkin lymphoma. The second class are ADCs, which are combinations of tumor-targeting antibodies with chemotherapy agents. The third are bispecific engineered agents. These are derivatives of antibodies that bring T cells together with tumor cells, thereby activating the T cells.
Trials with checkpoint inhibitors were halted due to safety data. Will they undergo further investigation?
In the interim analysis of the studies with pembrolizumab (Keytruda), it was noted that there were higher numbers of deaths in the experimental arm than in the control arm. The experimental arm consisted of a combination of pembrolizumab and pomalidomide (Pomalyst) or lenalidomide (Revlimid) and dexamethasone. The control arm was either pomalidomide and dexamethasone or lenalidomide and dexamethasone. The concern was that these deaths were due to immune-related adverse events, which is a known risk of checkpoint inhibitor therapy. The other concern was that there did not appear to be a survival difference between the experimental arm and the control arm.
These trials were only about 50% to two-thirds accrued at the time that these interim analyses were done. After reviewing the data, it was noted that there were some potential imbalances in the patient arms [because the trial had yet to fully accrue]. This was in terms of patient age, comorbidities, or prior lines of therapy. Nevertheless, it was prudent of the FDA to halt these trials for review. I don't necessarily agree with the decision by the sponsors to terminate the trials. [I think that’s] premature. It's fairly clear from the phase I/II trials that there was activity with these agents. It's pretty clear that immunotherapies are effective in multiple myeloma. We should have as many tools available to us as possible as long as they can be safely applied.
Ongoing studies are investigating combination therapy. We're combining things like daratumumab (Darzalex) with immune checkpoint inhibitors. Current clinical trials include nivolumab (Opdivo) and atezolizumab (Tecentriq), which are both FDA approved for certain solid tumor [indications]. It's important that we continue this line of work under appropriate safety review in order to find what the role for these powerful immunotherapy agents will be.
What are some potential targets under development?
There are 2 FDA-approved monoclonal antibodies for myeloma; one is targeting CD38, which is daratumumab. The other is targeting SLAMF7, which is elotuzumab (Empliciti). Both of these agents, particularly in combination, show excellent responses and long-term follow-up data. There are a number of antibody-based therapies targeting BCMA, similar to the chimeric antigen receptor (CAR) T-cell therapies. Some of these have shown excellent activity.