Sonrotoclax Combo Shows Promise for 11;14 Myeloma | Hang Quach, MD

My name is Hang Quach. I am a hematologist at Saint Vincent's Hospital, Melbourne in Australia, and I'm a professor of hematology at the University of Melbourne in Australia.

Today I'll be talking about the presentations that I presented at ASH.

The first presentation was the initial results of a phase 1b/2 study of a combination of a new regimen that's sonrotoclax together with carfilzomib and dexamethasone in a group of patients with the 11;14 translocation.

Now the cytogenetic 11;14 translocation is an important cytogenetic abnormality because it predicts for a responsiveness to a group of drugs called BCL2 inhibitors such as venetoclax.

Now, sonrotoclax is a next generation BCL2 inhibitor that is more potent than venetoclax. And previously we presented the initial result of our BGB-105 study that demonstrated that sonrotoclax and dexamethasone was quite effective in a group of heavily pretreated patients with the 11;14 translocation.

So we now present new data of another arm within the same study, which explores this new combination of sonrotoclax together with carfilzomib and dexamethasone, only for patients with the 11;14 translocation.

The reason behind combining sonrotoclax with carfilzomib and dexamethasone is that both carfilzomib and dexamethasone can potentiate the dependency of the myeloma cells to BCL2. So in a sense, carfilzomib and dexamethasone can sensitize the myeloma cells to respond better to sonrotoclax.

In this study, we presented the results of the 22 patients who we enrolled in the dose escalation phase of the study. These patients were quite heavily pretreated. They had the full prior lines of treatment. Some patients had as many as eight prior lines of treatment, and the majority of patients had exhausted all treatment options.

They'd had drugs belonging to the groups of immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. So essentially highlighting the challenging patient population that we involved in this study.

We explored multiple cohorts of doses, but the result we presented here at ASH was from three particular cohorts consisting of sonrotoclax, which is taken orally or by mouth daily in a 28-day cycle, at doses of 320mg or 640mg.

We combined that with carfilzomib, which is a very commonly used drug in myeloma nowadays. It's given intravenously, or through the veins, on days one, eight, and 15. And we also combined with dexamethasone, which is taken as a tablet once a week, and treatment was continued until disease progression.

What we saw was that the safety profile was quite favorable, in that when it comes to toxicity to blood counts, hematological toxicities, only over half of patients developed lowering of the blood count, but mainly mild.

In fact, the rate of severe neutropenia (low white cell count), anemia (low red cell count), and thrombocytopenia (low platelet count) were quite low. They occurred in 14% with neutropenia, 23% with thrombocytopenia, and 18% with anemia, which is relatively low compared comparatively to other trials and could be supportive.

Moreover, the rate of overall infections wasn’t as high as we had anticipated. Yes, infections did occur in just over half of all patients, but there were generally mild infections, such as COVID-19 or respiratory tract infections, and only around 1 in 4 patients developed severe infections, grade three infections. These infections were your common variety infections, mainly urinary tract infections and pneumonia, and they were very treatable.

Importantly, there was no signal for what we call opportunistic infections, the types of severe infections that you would get with immune suppressed patients, which we did not see in this study.

From a response perspective, we saw quite encouraging results. We saw an overall response rate of 86%, and a complete response rate of more than 38%, which is quite remarkable for what is a very heavily pretreated group of patients.

The median follow-up for these patients was around 10.4 months. And what we saw was that the duration of response: the majority of patients still responded, and the median duration of response was not reached. The median progression-free survival was also not reached. The majority of patients are still responding.

Overall, I think this initial data is quite promising and demonstrated that the combination of sonrotoclax, carfilzomib, and dexamethasone is a very deliverable, safe, and effective combination with very encouraging results for a group of patients with the 11;14 translocation.

I think this study is important because it brings us one step closer towards expanding effective and precision-based therapy for a group of patients with ongoing unmet need. This is largely because the group of patients with 11;14 translocation tend to respond less well to the commonly available drugs, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies.

So it's exciting for us.

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