ASCO 2015

Targeted drug daratumumab shows promise in heavily treatment-resistant multiple myeloma

Dr Saad Zafar Usmani - Levine Cancer Institute, Charlotte, USA

You’re talking about patients with multiple myeloma who have had the book thrown at them, aren’t you?

That is true.

What was the patient selection?

That is very true. We were studying patients who had received at least three prior lines of therapy or they were doubly refractory to an immunomodulatory drug or a proteasome inhibitor. Our median line of prior therapy for this study was five median prior lines of therapy. So, yes, this was a very refractory patient population.

So enter daratumumab. What is it and what does it do?

Daratumumab is a human monoclonal antibody that targets CD-38. CD-38 is highly expressed on myeloma cells.

Highly expressed, so why haven’t people been targeting it before?

That is an excellent question. For the longest time the myeloma research community has been longing to develop monoclonal antibody therapy. Unlike the lymphoma field where we have had successes with developing anti-CD20 monoclonal antibodies from the early ‘90s, the early efforts targeted other surface markers like anti-HER antibodies which were not very successful.

So could you tell me about the study, what was your approach and what did you do?

This study was an open label international multi-centre study. It was designed as a phase II study and it had two stages. During the first stage of roughly 34 patients two doses were evaluated for efficacy – 8mg/kg and 16mg/kg. The 16mg/kg dosing was more efficacious therefore we expanded that cohort to 90 additional patients for a total of 106 patients.

So tell me about the responses you got.

The responses, the overall response rate was 29% and we also saw stringent CR rates with the single agent in patients who have had multiple prior lines of therapy and are refractory to the available approved drugs. This is truly unprecedented for the field of myeloma.

Especially because they’d had just about everything else beforehand.

That is true.

You also used the word deep responses and deepening, what did you mean by that?

The current International Myeloma Working Group response criteria includes terminology such as partial response where you see more than 50% reduction in monoclonal proteins, very good partial response where you see more than 90% reduction, complete response is disappearance of the m protein but you may still have presence of free light chain ratio abnormality. And if you have no monoclonal protein, no serum protein or urine protein with fixation and a normal kappa-lambda ratio then it’s stringent CR. The reason why I’m bringing this up is it’s truly remarkable to see stringent CRs with monotherapy for this patient population. But we saw stringent CRs with daratumumab monoclonal therapy for this refractory population.

I have to ask you, though, about safety.

The safety is another unique feature for daratumumab. Being a monoclonal therapy our anticipation was we will not see major adverse or significant adverse events. All we saw for the most part were infusion related reactions, they were grade 1 and 2, mostly during the first or second infusion. Beyond that patients tolerated the drug beautifully.

Now you’ve told me you’re impressed, I’m impressed too. What are the clinical applications, do you think?

The clinical applications are profound because now we have a rituximab kind of therapy for myeloma. It can be potentially combined with available platforms of drugs such as lenalidomide and dexamethasone or Velcade and dexamethasone or Velcade, melphalan, prednisone and those kind of phase III studies are ongoing in the United States and in Europe.

So what do you advise clinicians to make of this at the moment?

At the moment I think once the authorities approve this therapy for the relapsed refractory patients, it is a fantastic option for those patients who have progressed on the available therapies. But we do anticipate that this therapy will make its way to the up-front setting over the next five years.

And what should doctors be taking home from this ASCO, this news you’ve just presented then, very briefly?

We are now entering the era of immunotherapy for myeloma patients. I use the term immunotherapy broadly but daratumumab is perhaps the first monoclonal antibody with single agent activity in myeloma. I anticipate that we are probably going to have several more immunotherapies being developed in the field. The advantage of immunotherapies is potentially very low adverse events and significant adverse events with those therapies. So I am really excited.