Keith, ever since we heard about the way that thalidomide did all sorts of amazing things for multiple myeloma it’s been intriguing to know that lenalidomide also does and in different ways and has different qualities. Can you tell me about your new study that’s putting the two head to head?

Yes. I’m representing at this meeting a study comparing melphalan, prednisone and thalidomide against melphalan, prednisone and lenalidomide or Revlimid. The concept behind this study was that lenalidomide, being a more potent drug with a different toxicity profile, might actually improve on the results. So that was the question we set out to address.

So what did you do? How many patients?

306 patients, one arm got melphalan, prednisone, thalidomide, the others got melphalan, prednisone, Revlimid. They both stayed on maintenance therapy until progression, which was another difference over what we usually do in standard practice.

The maintenance being?

Continuous thalidomide or continuous lenalidomide. The bottom line of this study, and the arms were balanced; an important thing for the audience to know is the median age was elderly, 75 years of age, so this was really a population in the United States in whom transplant would never be considered. The bottom line of this study is that they performed almost identically in almost every parameter – response rate, progression free survival, overall survival, really very little to tell between them. There may be a slight superiority to thalidomide, interestingly enough, but statistically not significant. What was different was the toxicity profile with lenalidomide proving to be a little bit less toxic when combined with melphalan, a little bit less myelosuppression but predominantly less constipation, peripheral neuropathy. Therefore the patients actually reported a better quality of life taking lenalidomide over thalidomide so, from that perspective, one could say that they’re both adequate partners with an alkylator to start off with but for toxicity reasons lenalidomide may be a better partner, for cost reasons thalidomide.

What about soporific side effects? That was an issue with thalidomide at one time.

Yes, I didn’t mention those. Of course, those are the usual things, sedation, constipation, peripheral neuropathy which one doesn’t really see with lenalidomide. On the other hand lenalidomide is more myelosuppressive and when you combine it with melphalan you have to use essentially 50% of the melphalan dose to be able to give it safely. So there is the trade-off there so that you’re using low dose melphalan with Revlimid versus normal dose melphalan with thalidomide which is probably why the two arms balanced each other out.

Of course doctors are used to managing toxicities in order to get effective treatments, aren’t they? So what might be your guidance coming out of this and your observations?

I have to put on my US hat right now, since I work in the United States, and tell you melphalan is gone, nobody uses melphalan in the United States anymore because we have access to bortezomib, we have access to lenalidomide in our newly diagnosed patients already. So this study is really, at this point, relevant for the rest of the world outside of the United States where melphalan remains a cornerstone of practice. I think there’s very little to tell between MPT, MPR and even melphalan, prednisone and bortezomib in terms of efficacy and overall survival. What is different is toxicity.

So what are your conclusions, then, coming out of this for practical medicine?

For practical medicine in the United States I think the trial took long enough that this is not really that relevant to our clinical practice except that it gives us a sense of the long-term toxicity of both drugs. One of the other things that it tells us is that adding maintenance, again this concept of continuous therapy, appeared to benefit patients compared to historic controls. Outside of the United States and Europe the message is that both regimens are acceptable but the patients feel better when they’re taking lenalidomide and if that’s an option I think that that would be a reasonable choice.

Globally they could be big implications though because some countries can afford one agent but certainly could not afford the other.

If you live in a country where the economics are prominent then this would tell you that thalidomide gives you the same outcomes as the more expensive lenalidomide, albeit that you’ll have some more toxicity with that regimen.

So what clinical messages should doctors take home from this?

The clinical message is there’s really very little difference between the two regimens overall but, as mentioned already, a little bit less toxicity, better quality of life for patients but either would be an acceptable choice.

And how has the advent of things like bortezomib changed the whole picture?

Bortezomib is the other drug that partners very well with melphalan prednisone; it has a different toxicity profile, mainly neuropathy; that can be somewhat abrogated by giving it subcutaneously instead of intravenously and by giving it weekly instead of twice weekly. It’s a very good choice as well, so as best we can tell in terms of overall survival there is really little to choose between the regimens. You could pick any one of them and it would be based on your tolerance of toxicity, convenience for the patient and cost.

So run that through me one more time - either thalidomide or lenalidomide or bortezomib?

They would all be good choices; again you’ll accept different toxicities with each one, probably with lenalidomide being the least toxic. On the other hand there is a cost issue and any one of them will give you the same basic outcome.

And you were looking at older patients, what about younger ones and those going on to transplant potentially?

Generally we don’t recommend a melphalan based therapy in patients going for transplant because it does cause toxicity. One thing we haven’t mentioned about our study is that there was an increased incidence of hematologic malignancy in patients who took melphalan, prednisone, thalidomide as a consequence of therapy because of the higher doses of melphalan. So, again, that would suggest a slightly safer profile would be with bortezomib or lenalidomide.

Keith, thank you very much.

You’re welcome, thank you.