Sagar Lonial, MD, discusses the future of monoclonal antibodies in multiple myeloma.
Sagar Lonial, MD
Monoclonal antibodies have shown significant potential for the treatment of multiple myeloma. Positive data on two of them, elotuzumab and daratumumab, were presented from two separate clinical trials at the 2015 ASCO Annual Meeting.
In the phase III ELOQUENT-2 trial, adding elotuzumab to lenalidomide (Revlimid) and dexamethasone was found to reduce the risk of disease progression by 30% in patients with relapsed/refractory multiple myeloma.
A phase II study of daratumumab, an anti-CD38 monoclonal antibody, also had positive results, with daratumumab demonstrating a 65% 1-year overall survival (OS) rate and a 29.2% objective response rate (ORR) in patients with double refractory heavily pretreated multiple myeloma.
OncLive spoke with the lead author on both trials, Sagar Lonial, MD, professor, executive vice chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute, to learn more about the impact of these trials and the future of monoclonal antibodies in multiple myeloma.
OncLive: Can you describe the goals of the ELOQUENT-2 trial?
Dr Lonial: ELOQUENT-2 is a randomized phase III trial trying to evaluate the benefit of elotuzumab in combination with lenalidomide and dexamethasone compared to lenalidomide and dexamethasone alone. It is really based on earlier phase I and phase II studies that we did at our center, which demonstrated that elotuzumab and lenalidomide were synergistic when given together and had a better ORR and longer progression-free survival (PFS).
At baseline, this study, which had 300 patients in each arm, demonstrated that approximately one-third of patients had high-risk disease at the time of initial presentation, and roughly one-third of patients were refractory to their last line of therapy, although it was an early treatment cohort. With elotuzumab, we demonstrated a 30% improvement in PFS, an improvement in ORR, and found suggestions that there were improvements in OS. It is too soon to have that group analyzed, but if you look at the absolute number of deaths so far, it favors the group that received elotuzumab.
Were there differences in toxicity between the two cohorts?
The only differences in toxicities between the two arms were infusion-related reactions in the elotuzumab arm. It occurred in about 10% of patients and is not unexpected for a monoclonal antibody and was easily mitigated with pre-medication.
What were the most significant findings from this trial?
We learned that elotuzumab has the ability to potentially mitigate or overcome high-risk disease. There are subset of patients with 17p deletion or t(4;14) translocation that appeared to gain equal benefit from elotuzumab, whether the genetic abnormality was present or not. Those patients in the lenalidomide and dexamethasone only arm didn’t do quite as well.
We also demonstrated that the response rate was independent of age and that the durability of the response rate was independent of age. Most importantly, if you took patients in either arm that had a partial response (PR), the durability of that PR was longer if they had received the antibody. That is different because, historically, if you get a complete response (CR) it doesn’t matter how you got there, the patient is going to do just as well. What we showed is, if a patient got a PR or a CR and they had received elotuzumab along with lenalidomide and dexamethasone, they stayed in remission longer than those who just received lenalidomide and dexamethasone.
Where do you see elotuzumab fitting in the treatment paradigm, in terms of sequencing?
In any disease in oncology, when you have a monoclonal antibody, it just gets used everywhere in every setting. Now that we have two, that will be absolutely true in myeloma, as well. It will be used across the board.
What is next for elotuzumab use in multiple myeloma?
This was the first phase III trial to be reported with elotuzumab. There is a second phase III trial that has completed enrollment called ELOQUENT-1, which involves newly diagnosed patients with myeloma. We are waiting for the data from that. There are trials administering elotuzumab to patients who are newly diagnosed in the transplant eligible setting combining it with RVD (lenalidomide, bortezomib, and dexamethasone), and there are other trials looking at it in the relapsed/refractory setting combining it with pomalidomide and bortezomib, as well.
What were the goals of the recent phase II study you led, which examined daratumumab as a monotherapy in multiple myeloma?
Daratumumab is an anti-CD38 targeting monoclonal antibody. Previous studies had suggested that 16 mg/kg was a good dose, so the first goal of the study was to determine if that dose was appropriate, or if 8 mg/kg would be just as good. We determined that 16 mg/kg given weekly for the first two cycles and then every other week after that was, in fact, the optimal dose.
The next goal was to identify what the response rate was in terms of relapsed/refractory patients. We showed that it was 30% across the board with a median of five prior lines of therapy for myeloma. Median duration of response was 7 months, and there were patients that were well over a year out now with ongoing CR.
What were the toxicities associated with daratumumab?
The most common toxicities with daratumumab were also infusion-related reactions, which occurred in about 40% of patients across the board. Ninety percent of that 40% occurred within the first dose. Once you get beyond the first dose, the incidence drops down, as it does with most monoclonal antibodies.
What is the future of daratumumab?
Daratumumab is currently in five randomized phase III trials, several of which have already completed and are now in follow-up. In these trials, daratumumab is combined with lenalidomide, bortezomib, and is examined in the smoldering setting, as well. I think daratumumab is going to be used across the board, as well. We just need to figure out how to combine them or properly sequence them.
Where is the future headed for monoclonal antibodies in myeloma?
Monoclonal antibodies offer a unique and different action from what we are used to using. This new mechanism of action is very important for those patients who don’t have other options. In the newly diagnosed population, it may offer us a higher percentage of patients who are cured.
Is there a space for additional monoclonal antibodies in this setting?
We have not yet fully explored the immune augmenting monoclonal antibodies such as PD-1, PD-L1, ICAM-1, and OX40. All of these are antibodies that should turn on immune effector cells. One of the real issues with myeloma, when it presents, is impaired immunity as a consequence of the disease itself. Anything we can do to restore that would be important.