18th Congress of EHA

Pomalidomide prolongs survival in refractory multiple myeloma patients

Prof Jesus San Miguel - University Hospital of Salamanca, Salamanca, Spain

Before we talk about the specific details of the MM-003 trial can you briefly outline the dilemma represented by the management of myeloma patients who relapse on or who are refractory to current standard therapies?

I think I should separate the concept of relapsing from the concept of refractory disease because nowadays we have many drugs that have shown high efficacy in the relapsed setting, drugs that can put even again the patient into a complete response that is maintained for years. This is the situation for which it was approved drugs such as thalidomide, bortezomib, lenalidomide, bendamustine and new drugs are coming, including monoclonal antibodies. But the situation is clearly different when you become eventually double refractory, as we call it, to proteasome inhibitors and immunomodulatory drugs such as lenalidomide. On top of this, these patients are already also refractory to alkylators. Then in the real world outside of centres of excellence that they have access to experimental agents, for these patients there is no chance.

So you can you outline, then, the background to the MM-003 study and what your main findings were?

The MM-003 trial was based on one drug that is one immunomodulatory drug, pomalidomide. It’s what we can call a third generation of immunomodulators. Pomalidomide showed initially clear activity and efficacy in the relapsed setting and then several phase I and II trials showed also efficacy in a fraction of refractory patients to lenalidomide and also to bortezomib. Then the obvious next step was to conduct a randomised trial comparing pomalidomide plus low dose dexamethasone, always the IMiDs, the immunomodulatory drugs, are combined with corticosteroids, versus what was considered the standard of care for these end stage disease patients, that was high dose dexamethasone. The study included 455 patients and the results have been clearly positive for the experimental arm for pom plus low dose dex. In terms of PFS, that was the primary endpoint, 4 versus 1.9 months, also in terms of response rate it was 31% partial responses versus 10% partial responses, 39% if you include the minor responses in the pomalidomide low dose dexamethasone arm. What is even more important is the benefit in overall survival – more than 12 months versus 8 months in the control arm. If you put all this together, plus the tolerability that was pretty good, no peripheral neuropathy, no DVT, a low rate of infection, a very low rate of discontinuation, and having an oral agent, all these speak in favour of a good opportunity for this type of patient because now we have a new standard of care for this end stage disease.

If you allow me to add something, it’s that hopefully this is going to be just the beginning of a good story because what I think is immediate, several groups have decided to combine pom-dex, pomalidomide dexamethasone, with other agents. The obvious other agents are the proteasome inhibitors but also alkylators and probably the triplets are going to be more efficient. Eventually these drugs should be tested also in the newly diagnosed patient. Then I think we have a good panorama for the future for myeloma because now we have this third generation approved, the United States has already approved the second generation of proteasome inhibitors, that is carfilzomib. As I already mentioned to you, the monoclonal antibodies, elotuzumab – amazing results in combination with lenalidomide. And in this congress there is going to be presented data on daratumumab and the CD38 monoclonal antibody as a single agent is working in myeloma. Then I feel optimistic.

So from what you say, then, this seems to represent a genuine therapeutic advance for these patients?

Yes, clear.

And can you say where you think we will be in twelve months’ time, perhaps?

Do you mean pomalidomide or all the myeloma spectrum?

All the myeloma advances that we’re seeing at this meeting.

I like to be prudent. Some people say, ‘OK, are you going to cure myeloma?’ No, we’re still far away from this situation. Has myeloma become a chronic disease? No, unfortunately no. Some patients may be already cured and in some patients the disease is well controlled for many years but in some other patients this is not the case. But if you look back ten years ago when thalidomide was introduced as a new agent for the treatment of myeloma patients, in ten years we have already four new drugs for these patients, why not have another four or five drugs in the next ten years and the appropriate combination of these drugs changing the current scenario of the myeloma outcome that this still is quite a devastating disease.

Dr San Miguel, thank you very much indeed.