Transcript
Hi. My name is Jonathan Kaufman. I'm an Associate Professor of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia.
We've been studying venetoclax in multiple myeloma for several years. In the laboratory, we had predicted that venetoclax, or BCL-2 inhibition, would likely be more effective in a subset of patients, those patients who have the (11;14) translocation.
There was a Phase 1 study that was done and published several years ago. The lead author was Dr. Shaji Kumar. In that study, they looked at all-comers. We had predicted that it was more likely for the (11;14) patients to respond to venetoclax. While the study was done for all-comers, ourselves and several investigators only accrued patients with (11;14).
In this relatively small Phase 1 study, 30 percent of the patients had the (11;14) translocation, when, in an unselected patient population, you'd expect it to be closer to 15 percent. In that 30 percent of patients, the response rate for the single-agent venetoclax was 40 percent.
In the other patients, who didn't have (11;14), the overall response rate was 6 percent. That was really our first clinical proof of what we had predicted in the laboratory.
We asked the question, "What can we do to make more patients (11;14) respond to venetoclax?" We went back to the laboratory and started to use combinations of therapies. We actually found that dexamethasone made more myeloma patients sensitive to venetoclax. We have a paper published that describes why that's the case.
It's not that dexamethasone works on its own in this particularly well, but it shifts more patients to responding to venetoclax. That's why we designed, initially, a cohort of patients. Then we designed an additional Phase 2 study of combining venetoclax and dexamethasone in patients with relapsed and refractory (11;14) multiple myeloma.
Again, there were two parts of the study. The first part of the study looked at a group of patients who, on average, had 3 prior lines of therapy and a very small percentage of these patients had prior daratumumab. In that group, we did see a significant increase in response rate, up to 65 percent.
When we went to a later line, median prior therapies of 5 prior lines of therapy, and almost 90 percent of the patients refractory daratumumab, the response rate was close to 50 percent. It ended up being 48 percent.
We were very pleased with these results, again demonstrating this was really the first time in a prospective manner that we could use predictive medicine to identify the right treatment for a patient in myeloma. This is really the first time where we identified a biomarker, we selected a treatment, and we had a significant improvement in response rates.
From a tolerability standpoint, it was very tolerable. We saw an impressive time to progression, progression-free survival, and overall survival, particularly in the patients who responded.
There was a huge difference in the patients who responded and who didn't respond, in terms of their survival, which suggests to us, biologically, not only did our treatment work in a short-term perspective from a response rate, but actually allowed patients to live longer.
An interesting finding was that of the patients who had deletion 17p, which is an additional high-risk marker, also 50 percent of the patients responded. It tells us that response is independent of other high-risk features like 17p and 1q.
Our plan from here was held back a little bit because of what's known as the BELLINI study. The BELLINI study, again, was a study taking all-comers and randomized between bortezomib and dexamethasone, and venetoclax, bortezomib, and dexamethasone.
They found that while the progression-free survival was improved, the overall survival was actually worse with the addition of venetoclax. We had to go back to the drawing board on this. Again, the drawing board means refocus on the (11;14) patient population.
Right now, there ended up being a hold on all studies in venetoclax that has now been lifted by the FDA.
We have multiple randomized clinical trials right now asking the question, "Where does venetoclax fit?"
Firstly, we're now studying venetoclax in only (11;14) patients. There is an international study of venetoclax/dex versus pomalidomide and dex.
There are smaller Phase 2 studies of daratumumab/venetoclax/dex versus daratumumab/bortezomib/dex. There's a small Phase 2 study of venetoclax/carfilzomib/dex versus carfilzomib/dex. There's a study of venetoclax/pomalidomide/ixazomib/dex versus pomalidomide/ixazomib/dex. All of these (11;14). This is where we are in terms of the ongoing development of the drug.
In terms of clinical practice right now, I wouldn't say never, but I rarely use venetoclax and dexamethasone outside the context of a clinical trial. There are cases where it's appropriate, but it's very important, if you're going to use this outside of the context of clinical trial and outside of its labeled indication, that you very carefully counsel the patient that there is still an unknown risk, particularly associated that we saw with the prior study.
I think when all this is said and done, we are not going to see the same decrease in survival in the venetoclax arms when we pick (11;14) patients, but that's yet to be proven in the context of a clinical trial.
We're really excited about the potential of BCL-2 inhibition in multiple myeloma, particularly with patients with (11;14). We're still actively trying to understand who the right patient is for the drug and really identify biomarkers that can help us further refine venetoclax use in multiple myeloma.
