Early phase 1/2 results with oral proteasome inhibitor MLN9708 in myeloma

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Published: 15 Jun 2012
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Dr Sagar Lonial – Emory University, Atlanta, USA

Dr Saga Lonial talks to ecancer about the first oral proteasome inhibitor at the ASCO 2012 Annual meeting in Chicago.


Similar to bortezomib, but administered orally, MLN9708 is the first oral drug to go into clinical trial for myeloma. MLN9708 is boron-based making it a reversible inhibitor.


Current trials using the experimental drug aim to determine the dosage and efficacy in myeloma. Patients receiving the drug have already been heavily treated with commonly available agents and had high efficacy, with very low rates of neuropathy, when used in combination with other drugs.


ASCO 2012

Early phase 1/2 results with oral proteasome inhibitor MLN9708 in myeloma

Dr Sagar Lonial – Emory University, Atlanta, USA

Professor Lonial, it’s good to get your input here because you’ve been presenting, you’ve been conducting research, on the oral proteasome inhibitor, it’s known by the letters MLN9708. It’s an early study, phase I/II, what have you been doing and why? Now this is presumably something like bortezomib but oral?

Correct. MLN9708 is the first oral proteasome inhibitor to be tested in clinical trials in myeloma. What it does, it is structurally slightly different from bortezomib but it is a boron based proteasome inhibitor in the sense that it is also a reversible inhibitor, it has similar pharmacokinetics and similar activity to bortezomib but is delivered in a different mechanism. What we did in this trial was enrol a total of 58 patients in a phase I and phase II experience to try and understand what the doses and potential efficacy of this oral agent given by itself is in the context of relapsed refractory myeloma.

And what have you found so far?

What we have discovered is that a) it’s an active drug and, remember, when you put in the response rates that I reported on earlier today, in the context of a single agent, there are no steroids in this regimen, there was no other therapy, just the oral proteasome inhibitor, we did see responses somewhere around 13-15%. About 50% of patients had stable disease. This trial, overall, was a very heavily pre-treated group of patients with a median of 4.5 prior lines of therapy, median time from diagnosis of about five years. All of them had seen most of the commonly available agents. What we discovered was not only efficacy but a very different safety profile from what we saw with bortezomib.

So is this something that you would use in refractory patients primarily or do you see it being introduced into your standard regimens as it proves its worth?

I think that’s a great question. At this meeting there are presentations combining 9708 with lenalidomide and dexamethasone in newly diagnosed myeloma patients and the response rates are phenomenal. So I think it probably is somewhat equivalent to bortezomib in terms of efficacy but it’s able to be delivered orally instead of IV and it has a very low rate of neuropathy.

That’s an alternative, then, to the very successful RVD approach you’ve been using in your establishment?

Correct, that is correct, yes.

What do you counsel doctors to be thinking about this, then, at the moment?

I think right now, obviously, it’s a very early phase study so this is not easily available out in the community, it’s only available through clinical trials. But what I would suggest is that there are phase III trials testing 9708 plus len-dex versus len-dex and placebo for newly diagnosed and relapsed patients that I think would be great for community physicians all over the world to potentially enrol on.

You said that neuropathy is lower, what about other toxicities compared, of course, to bortezomib?

The most common toxicities we saw with this was fatigue, which is common to most anti-cancer regimens; thrombocytopenia, so reduction in platelets, which was not dissimilar from what we saw with bortezomib and the third was rash. There was a little bit more rash incidence in 9708 than we saw with bortezomib but it was tolerable with topical steroids and, again, we saw a much lower rate of neuropathy. No patient on this study had grade 3 neuropathy.

We’ve seen a lot of progress in the treatment of multiple myeloma in the past few years and some very good therapies around so what do you sum up as being the main points that busy cancer doctors should get out of your new presentation of an oral proteasome inhibitor possibly being added to the regimens, or substituted?

Yes, it’s really encouraging data. What we’re seeing is bortezomib was the first drug on the scene, clearly an effective regimen, does have some toxicity issues that ultimately limit your ability to deliver proteasome inhibition for a long period of time. Carfilzomib is a second generation proteasome inhibitor, slightly different safety profile, but is also IV. What I think this drug adds in is a third version, if you will, easy to administer being oral and less neuropathy so fewer adverse events and toxicity. I think this is great news for our patients.

Sagar, it’s very good to talk to you. Thank you for joining us on ecancer.tv.

Thank you.