Anti-Bcl2 therapy shows promise for relapsed/refractory multiple myeloma

Published: 5 Dec 2015

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Dr Shaji Kumar - Mayo Clinic, Rochester, USA

Dr Kumar talks to ecancertv at ASH 2015 about the potential use of the oral Bcl-2 inhibitor venetoclax in patients with relapsed or refractory multiple myeloma.

In the interview he notes that venetoclax has been studied in clinical trials in chronic lymphocytic leukaemia (CLL) but there is evidence to show that the Bcl-2 protein that it targets is also expressed by myeloma cells.

Dr Kumar talks about two studies presented at the meeting investigating the use of venetoclax in patients with relapsed/refractory multiple myeloma. The first, a phase I/II study involving 37 patients, aimed to test the safety and find the best dose of the drug to use as monotherapy. The second, a phase Ib involving 41 patients, looking at using venetoclax in combination with bortezomib and dexamethasone.

Preliminary results of these trials suggest that venetoclax had a tolerable safety profile with no new safety signals. They also suggest the drug has potential single agent activity and might work well in combination with bortezomib and dexamethasone.

ecancer's filming at ASH 2015 has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

ASH 2015

Anti-Bcl2 therapy shows promise for relapsed/refractory multiple myeloma

Dr Shaji Kumar - Mayo Clinic, Rochester, USA

Venetoclax, it’s a new, relatively new, drug. Can you tell me what you’re doing with it here in the setting of relapsed or refractory multiple myeloma? You’ve got a couple of studies, tell me what you were trying to investigate with these.

So venetoclax, or ABT-199, is an oral inhibitor which is a specific inhibitor of Bcl2. It has been in clinical trials for several years now, mostly in the CLL space but more recently there have been clinical trials that are being done for multiple myeloma as well.

Why are you hoping it will work in multiple myeloma then?

A lot of the myeloma cells actually do express high levels of Bcl2 so there’s a good reason to believe that this drug might have an activity in multiple myeloma as well.

You’ve got a couple of studies, one is using this drug together with bortezomib and dexamethasone, the other using it as monotherapy. Can you tell me about both of those two studies?

Sure. The venetoclax, or the ABT-199, single agent study is essentially a phase I/II study that’s examining the best dose of venetoclax that can be given to these patients. We also want to see if there’s any signal in terms of efficacy. So roughly about 60 patients have been enrolled on this study; we know what is the maximum tolerated dose, it’s about 200mg daily, and that actually is not the maximum tolerated but that was the planned maximum dose in the study and we did not see any dose limiting toxicity with this drug.

What did you see?

The main side effect has been some GI side effects and some drop in blood counts.

What did you see in terms of efficacy then?

We saw five responses among the 60 patients which included two patients with complete response and three patients with a very good partial response with the single agent venetoclax.

So there’s response with single agent, what about the combination work then?

The reason why we looked at the combination is because the two synergise in the in vitro pre-clinical studies. There are some mechanisms for why the bortezomib can make ABT-199 work better or the other way around. So the combination study also we did not reach a maximum tolerated dose and the expansion phase is using the maximum planned dose. The regular dose of Velcade is used in these clinical studies. Now, in terms of efficacy in patients who have never seen a proteasome inhibitor all of them had a response. In patients who had previously seen bortezomib but have not become resistant to bortezomib we did see about 70% response rate, but a very low response rate in people who had previously been refractory to Velcade. But overall the combination seems to be fairly interesting in terms of its efficacy and its tolerability.

What, then, do you think this might be telling cancer doctors about the potential clinical use of this oral Bcl2 inhibitor?

I think the oral Bcl2 inhibitor is probably going to have a role to play in the multiple myeloma field but obviously we need phase III trials and those are being planned in combination with bortezomib to see if we can actually get this drug to the patient.

Now, I think I noted somewhere that you detected, as a conclusion, no new safety signals?

Right, we don’t see any major issues. It’s very well tolerated.

As conclusions go, no new safety signals isn’t telling you anything positive, is it?

No, it is. It is because now we have… previously we had a very small cohort of patients and now we have a much larger group of patients that are being treated in these clinical trials.

What might it promise in terms of efficacy?

I think there might be some biomarkers that could go with it, that is very exploratory right now. So there is a possibility we can identify patients who respond better to this drug. If that does pan out then you actually could have a biomarker driven treatment selection.

So what should doctors take note of, in summary, from your findings so far?

The main thing is it seems to be an exciting molecule and stay tuned for the phase III trials.