Multiple myeloma advances for the future suggested by phase I clinical research
Dr Jesus Berdeja – Sarah Cannon Research Institute, Nashville, USA
My name is Jesus Berdeja and I am at the Sarah Cannon Research Institute based in Nashville. I’m the Director of Multiple Myeloma and I’m in charge of conducting and creating clinical trials in multiple myeloma from phase I, first demand, to phase III.
Overview of your phase I study of lorvotuzumab mertansine in combination with lenalidomide and dexamethasone
The drug itself is an antibody drug conjugate. The antibody is targeted towards CD56, which is a protein on the surface of myeloma cells and it is linked to DM1 which is a vincristine analogue. So the way the drug works is it binds to CD56 on the surface of the myeloma cells, it gets internalised, the DM1 gets released and it kills the cell from the inside out. In the phase I trials that were performed with the single agent, the drug was well tolerated; they were able to go up to doses up to 112mg/m2 but what was seen, as would be expected, is peripheral neuropathy. So as you went up on the higher doses, the more peripheral neuropathy was seen. Now most of these patients had underlying peripheral neuropathy from prior therapies and from their disease as well but there definitely was an escalation, it was seen; mostly grade 2 neuropathy, there were one or two patients that had grade 3 neuropathy. What we saw in this current combination mirrors that. The most troublesome side effect that we saw in this combination was peripheral neuropathy; again most of them were grade 2 peripheral neuropathies and 75% of patients had an underlying grade 1 neuropathy when they started on trial. In terms of other side effects, most of the side effects were likely attributable to the dexamethasone-lenalidomide, they were fatigue, hyperglycaemia - normal or routine side effects that we see with those combinations. In terms of side effects truly attributed to the actual study medication, I think the neuropathy is probably the most salient.
How effective is this combination therapy?
This was a very effective combination. There were 44 patients enrolled and 39 were evaluable that actually received a whole cycle of the therapy. We saw responses at all dose levels including the lowest dose level tested at 75mg and the highest dose level. We actually chose to expand the 75mg/m2 dose level; it was just as effective as the higher dose levels with less neuropathy. Of those 39 patients that were evaluable, 60% had a response, at least minimal response or better, and we actually had about 30% of patients achieve better than or equal to a VGPR.
What are the next steps in clinical research?
The next step with this combination is taking it to an earlier population. I think a lot of the toxicities that we’re seeing are difficult to interpret because of underlying toxicities already present. This is an effective, active medication that can be combined and that’s what this study proved. So taking it to the earlier phases, perhaps up front, perhaps just one prior therapy, is the next step in this combination. The other thing I would also argue is we haven’t quite determined how to best use this medication, whether it can be used as a maintenance type therapy or not. So the duration of the treatment also needs to be investigated further.
What is the take home message for the multiple myeloma specialist?
I think there are a lot of exciting things going on in myeloma at this time. Everyone is obviously very well versed in the IMiDs, lenalidomide and thalidomide, and the proteasome inhibitors, bortezomib. There are now newer generations of those drugs that are being developed, including carfilzomib, which was just FDA approved here in the United States, which show significant activity with much less toxicity. Pomalidomide is coming down the pipe as well, it will probably be FDA approved soon but beyond that actually the proteasome inhibitor scene is exploding even further in that the drugs are now being developed orally and there are two drugs, two oral proteasome inhibitors, that have presentations here at ASH that are showing significant activity with very little toxicity with hardly any neuropathy which is very promising. So I think what is happening, at least from the backbone of therapy that we have now, is that we will have more effective, less toxic medications for our patients and then beyond that there is a lot of activity with antibody-based therapies, with antibody drug conjugates, like the one we just talked about, and with a lot of more directed therapies at the cellular level that hopefully will be yielding even more impressive results to these backbones that are becoming less and less toxic.