The latest for Multiple Myeloma

Professor Paul Richardson – Dana Farber Institute, Boston, USA

A great deal has happened in San Diego that’s very exciting and, I think, very good news for patients. We had a very busy session this morning looking at the new proteasome inhibitors that are now in development, ranging from the oral boronate peptide MLN9708 which has shown activity and safety as an oral proteasome inhibitor in relapsed refractory patients. In combination with lenalidomide the results have been particularly exciting and we’re very, very hopeful that this particular agent will come forward fairly rapidly in the therapeutic armamentarium.

The same session we saw presentations also on other novel combinations, including elotuzumab and lenalidomide; we saw conventional chemotherapy being given with lenalidomide in the form of bendamustine. So we’re seeing a whole array of different drugs being brought together that actually continue to show promise for treatment. Particularly later today there will be sessions on pomalidomide and combinations with bortezomib and other drugs such as panobinostat which are showing that these second and third generation agents are really continuing to show great promise.

What are the details of the PANORAMA-2 trial?

In the PANORAMA-2 trial, basically this is a multi-centre phase II study in which we’ve combined bortezomib and panobinostat and dexamethasone. The rationale behind this is that one of the escape pathways that myeloma utilises, we believe, in the context of becoming resistant to bortezomib is where, when you block the proteasome, a pathway called the aggresome is activated and it uses it as a means of protein degradation to escape the effect of proteasome inhibition. Deacetylase inhibitors, broadly, inhibit this pathway by modulating the aggresome and panobinostat is one of the most potent in this class. Essentially pre-clinical work had informed a phase I trial that had showed that you could safely combine panobinostat administered three times a week with bortezomib in its classic schedule. What we also learnt from that study was that if you gave the panobinostat for three weeks in a row there were too many side effects in that third week so we took that out. So patients received three doses of the pill a week for two weeks and have one week rest and then they receive bortezomib on exactly the same schedule. What we found is that in bortezomib refractory patients, truly refractory, they all had to be to come into the trial, we’ve seen a very robust response rate and about a third of patients appear to respond, which is quite remarkable given the rigour with which we’ve allowed patients into the trial – they must only be truly refractory to Velcade. So to see bortezomib failure reversed in a third is a remarkable proof of principle. The other piece of it has been that these responses have been durable and, excitingly, we’ve seen this combination work when very powerful combinations like lenalidomide, bortezomib and dexamethasone, so-called RVD, has failed. So it’s really nice to have a powerful combination as a back-up for when some of our other combinations fail to deliver.

Do you have other highlights from ASH 2011?

I think the pomalidomide story is worthy of particular mention. That’s the combination of pomalidomide and low doses of dexamethasone, particularly relevant because the original phase I work was done by Matthew Streetly and Stephen Schey at Guys Hospital in London where they were able to show the activity of the drug and define a tolerated dose in relapsed patients. What we then did was to take the dose and schedule, modify it and actually escalate the dose to 4mg three weeks on and one week off, successfully combine it with low doses of dexamethasone and test it in a truly relapsed and refractory population who constituted an area of what we call exquisite unmet medical need. In other words, these are patients whose disease has been multiply relapsed and they’ve become resistant, not only to bortezomib, but also to lenalidomide. And because of that unique niche of patients, which is not a small one, it’s actually a growing one, we were particularly gratified to see that pomalidomide was able to induce, just as a pill, in combination with low dose dexamethasone about a 30% response rate, in fact more than that to be precise, 34% response rate, which we were very encouraged by with some very promising overall survival data which we think is a very positive step forward for patients because obviously pomalidomide constitutes a third generation IMiD. The first generation IMiD, arguably, is thalidomide; the second generation IMiD is lenalidomide and the third generation is now pomalidomide; interesting enough, in the laboratory it is the most potent IMiD. So now clinicians have choices of which they can use and pomalidomide, therefore, provides us with a really nice agent that’s there once lenalidomide has failed. And that, I think, for patients is extremely good news.

There’s also a European trial underway?

There’s a European trial, randomised trial, comparing pomalidomide and dex to dex alone in relapsed and refractory patients, recognising that in Europe the options for patients are different. Generally speaking there are fewer options and so, therefore, the population in Europe is different. In the US we’re blessed by having multiple different options that we can pursue, so our study was specifically in the United States and in the European study, that is a randomised study, but very importantly for patients who are receiving high dose dexamethasone, if that treatment fails them they have access to pomalidomide, that’s very important, in a companion trial. So I think that that particular randomised trial in Europe will hopefully clarify for the European regulators the efficacy of the drug because that’s what this trial has primarily been driven by, the need for the regulators in Europe to be satisfied that this new drug combination really is making a difference. In the US we’ve had a single arm experience which is important and then we’ve done a randomised phase II in which both groups of patients received pomalidomide. We are looking to do a randomised trial earlier because we think that’s the right place to test, for example, bortezomib and dex versus bortezomib, dex and pomalidomide. That probably will be our forward strategy with pomalidomide going forward, as I say, with that approach.

So there’s promising possibilities for Multiple Myeloma patients?

Absolutely, and I think what’s particularly exciting about pomalidomide is that it’s well tolerated, the side effects very manageable and it has the convenience of just oral dosing. There is another very nice paper from our colleagues in France showing that the schedule of three weeks on, one week off, which we had developed is, in fact, the correct one. They did a randomised phase II and showed that the continuous dosing was more toxic and associated with a shorter duration of response because of that than if you go to three weeks on and one week off in which the tolerability is better and that results in a longer duration of response.

Any other highlights?

There are multiple trials and there are obviously very exciting data with carfilzomib and lenalidomide in the up-front setting from my colleague, Andrzej Jakubowiak, which is a tremendous example of rational trial design based upon very exciting pre-clinical evidence that proteasome inhibitors and IMiDs are synergistic. We’ve obviously shown that with the combination of Revlimid and Velcade and now carfilzomib and Revlimid seem to be working out to be a very good partnership as well, which is great. On the flip side of that we’re also presenting a paper where we’ve successfully combined bortezomib with another pill, a simple pill, called perifosine that targets a unique pathway, AKT, as well as also activating a protein called junk. And in that context that combination appears to be synergistic and we’re presenting long-term outcome data from our phase II trial showing that in relapsed refractory patients we have median survivals of two years with this combination. So I think there is a lot happening in the myeloma sphere but the exciting thing for patients is that we have many options to choose from, going forward, and it’s coming forward also in a very organised and structured fashion so that we hope we’ll be able to deliver these new agents as quickly as possible to where they’re needed.