ASH 2015

First targeted therapy for multiple myeloma effective against hard-to-treat disease

Dr Torben Plesner - Vejle Hospital, Vejle, Denmark

Could you tell me, first of all, what is the importance of daratumumab? What exactly is this substance?

Daratumumab is a monoclonal antibody that is directed against the CD38 molecule. This molecule is very abundantly expressed by myeloma cells so it seems to be a very good target for killing the myeloma cells.

So what were you trying to do here in the situation of multiple myeloma that is relapsed or refractory and has been treated before?

We are introducing a new way of killing the myeloma cells. What we have been using in the past is alkylating agents, old-fashioned chemotherapy, steroids, proteasome inhibitors as newcomers, IMiDs as newcomers, but when we have used all them we are left without weapons against the myeloma. So now comes the monoclonal antibody in to help us and we have shown in a monotherapy study called GEN501, and later colleagues in America have shown in the SIRIUS trial, that single agent daratumumab has very significant activity on its own against myeloma.

So could you tell me what you did in this study?

In this study it was the first time we combined daratumumab, which has single agent activity against myeloma, with another important drug in myeloma treatment, lenalidomide together with dexamethasone. So this is the first combination study with daratumumab.

And what did you find?

We started with a dose escalation study from 2 to 4 to 8 and 16mg/kg of patient’s bodyweight and we found there was no sign of maximum tolerated dose, there was no toxicity to speak about. So we could really go out in a phase II trial, which is the one I’m reporting here, with a 16mg/kg of patient’s bodyweight to treat an increased number of patients, 32 patients in all, with this combination of daratumumab, lenalidomide and dexamethasone.

So what have you established so far? This is early days yet, isn’t it?

Yes, it’s early days but we have established safety which was the first important step. So these drugs go along together very well in the treatment of myeloma. The treatment is well tolerated and the patients have a very good quality of life when they are on treatment. The treatment can continue for a very long period; we have patients continuing beyond two years now on treatment with a very excellent response.

So there seems to be benefit in giving the drug as monotherapy, it looks safe in combination, what do you think this is going to result in clinically?

We see enhanced responses in terms of quality of response and we see prolonged duration of response by the combination.

What do you think doctors should be making of this at this stage?

We are now going into phase III trials, they are already up and running. The phase III trial in the relapsed refractory setting has completed inclusion. The first line phase III trial is ongoing and we are recruiting patients for that. So the results of the phase III trial will guide us about the place that daratumumab should have in the therapy of multiple myeloma. My personal opinion is that daratumumab will be for myeloma what rituximab has been for lymphoma treatment in the past years.

We’ve had very good progress in multiple myeloma so do you really think this can be a big step forward at the moment?

I agree that we had great moves forward with the advent of proteasome inhibitors, with high quality IMiDs such as lenalidomide and pomalidomide, this is another major step ahead, adding on an antibody to the combinations.

In terms of efficacy, prolonging life, what kind of an impact might it conceivably make if further studies go ahead well?

I have my patients on treatment for very prolonged periods of time, living very good quality of life, showing up in the outpatient clinic once a month for half a day of treatment and they go home happy and in remission and seemingly remain in remission.

And we need to find out for how long.

How long, yes.

So what should doctors take home from this right now?

They should follow the development from the clinical trials very carefully. My expectation is that this will be a major part of the future treatment of multiple myeloma so they should get interested in the use of daratumumab, get familiar with the way it’s used, the problems that can be associated with the use of daratumumab such as blood typing for blood transfusions, there is an issue. There is also an issue with assessing CR because daratumumab will show up in the serum of the patients as a minor m component, very little but it’s there so in some cases it’s difficult to claim CR for the patients. But that kind of detail people should be aware of. Then when that is set it’s an easy drug to give to the patients and without major side effects.