Update on the development of proteasome inhibitors

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Published: 19 Dec 2011
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Dr Philip McCarthy – Roswell Park Cancer Institute, USA

Dr Phillip McCarthy takes time at ASH 2011 to discuss recent advancements with proteasome inhibitors in cases of multiple myeloma. 


Dr McCarthy highlights the millennium compound, an orally administered drug that has been tolerated well by patients and could lead to another novel agent for induction and salvage in myeloma patients. In addition, millennium 9708 has shown efficacy in early studies with relapse and refectory and will likely be combined with other agents, such as steroids, in clinical use. Other drugs Dr McCarthy discusses are marizomib, a proteasome inhibitor with a better toxicity level; lintuzumab, an anti myeloma drug used in relapse and refractory, and pomalidomide. Dr McCarthy concludes that these new developments give patient and doctors much more choice for treatment options.

2011 ASH Annual Meeting, December 10-13, San Diego, USA

Update on the development of proteasome inhibitors

Dr Philip McCarthy – Roswell Park Cancer Institute, USA

There is, as usual, a variety of different and exciting new abstracts at this year’s meeting. There’s a follow-up on the maintenance trial, the MM015, which is the Italian study looking at MPR followed by R, M being melphalan, P being prednisone, R being Revlimid or lenalidomide, compared to MPR without lenalidomide, the placebo maintenance, and then MP also without maintenance. The progression free survival in the MPR-R arm is quite prolonged when compared to the other two arms and now there is a trend towards an overall survival benefit in the MPR-R arm which Dr Palumbo and his group will be discussing at this year’s meeting. That’s very exciting.

The French, the IFM-0502 study has been updated, there is also a major time to progression benefit with the lenalidomide arm. This is a trial looking at transplant after induction therapy followed by then lenalidomide or Revlimid maintenance and the placebo arm is much inferior when it comes to time to progression. There is still not an overall survival benefit when compared to CALGB 100104 which is not being presented this year but has been presented last year and has now been submitted as a manuscript which does show a survival advantage for lenalidomide compared to placebo.

Can you highlight some of the new data coming out?

The thing that’s very interesting about multiple myeloma is that patients who have received prior therapy so, for example, even with novel therapies such as with an IMiD or a proteasome inhibitor, can see those drugs again in the context of another agent. So, in other words, when HDAC inhibitors are added to lenalidomide and steroids, gratifying responses are seen in patients who have either relapsed or relapsed refractory disease. So this is quite exciting, so it allows investigators to be able to combine new agents with old agents and generate very nice responses that lead to good outcomes for patients. So, for example, vorinostat, based on pre-clinical data out of Ken Anderson’s lab, has been added to lenalidomide and dexamethasone and the results will be presented on Monday but it appears that the results appear to be positive but we’ll find out for sure on Monday afternoon.

Could you explain “the millennium compound”?

Which has shown that, again, added to other agents generates good responses. So this is also quite exciting news, so we now have another proteasome inhibitor which is an oral agent that appears to be very well tolerated which we hope will lead to another novel approach for both induction as well as for salvage in myeloma patients. That appears to have a nice efficacy in early study results presented by the Dana Farber group in a collaborative effort with other investigators, so this is in relapsed and refractory patients. So this is another compound, another proteasome inhibitor which will likely be combined with other agents, particularly with steroids, to see if we can generate some good responses in patients who have otherwise failed frontline therapy.

Marizomib is another proteasome inhibitor, also the Dana Farber group has investigated this in a phase I/II effort. They found that it has a different toxicity profile than bortezomib even though it is a proteasome inhibitor, that’s exciting. So that allows people to be able to use this in a different way and alone or in combination with low dose steroids it appears to have efficacy, again, in the same type of patient population with relapsed and refractory disease. Very exciting as this is an antibody with anti-myeloma effects. Again, when combined with steroids and lenalidomide, has generated some very nice anti-myeloma effects, again in a relapsed refractory patient population. So this is very good news because we’ll now be able to use a new type of agent which we’ve not been able to use before in a multiple myeloma patient population.

What is the message oncologists should take from this meeting?

I think that there are a variety of new agents, pomalidomide, which has been reported at last year’s ASH meeting and as well at this year’s ASH meeting, hopefully will be approved for patients in the relapsed setting. This is a novel IMiD, has some myelosuppressive effects; it appears to salvage patients who have seen both lenalidomide and bortezomib, so that’s very exciting news. So what we’re seeing at this year’s ASH are the drugs that we hope to see available for all clinicians in maybe two or three years, we’re also seeing some of the agents that were presented last year, very exciting results that have continued to be impressive. Hopefully we’ll see some approval by regulatory agencies for their use in the clinical setting.

I’m hopeful that we’ll see pomalidomide available for relapsed patients. We would like to see the carfilzomib, the Onyx compound, available also for patients as it is a proteasome inhibitor with a different safety profile than bortezomib. We may see some new indications for lenalidomide, potentially in the maintenance situation so that this will allow patients and doctors to have much more choice for managing multiple myeloma.

What do these advancements in proteasome inhibitors mean for patients?

I think this is a very exciting time for myeloma patients. When I was a Fellow, back in the ‘80s, the median survival for myeloma patients was about three years. In other words, if you had a hundred myeloma patients requiring therapy, fifty would be alive at three years, that’s very disappointing. Now the median survival is up to eight years and beyond so we need to do better, of course, but with all these new agents I think our problem will be, and this is a good problem to have, is how do we combine all these agents to provide the best efficacy and the best outcome for myeloma patients?