The idea is that cyclophosphamide, it’s an inoculating agent that we’ve been using in myeloma for quite a long time; it’s almost one of the first treatments that was tried in myeloma. Now we are using alkylating agents very little, in fact we are using very few of them, but they combine pretty well with new drugs, mainly immunomodulatory drugs. So they combine very well with lenalidomide and pomalidomide in several settings and increases the efficacy of these agents. It has been also tried with proteasome inhibitors, carfilzomib is one of them, but there are not many clinical trials following this possibility so we wanted to do a trial in which we could see if one of the standards of care, which is carfilzomib with dexamethasone, could be enhanced somehow using cyclophosphamide with it. So we did this phase II trial comparing carfilzomib dexamethasone with carfilzomib, dexamethasone plus cyclophosphamide.
What were the main aims and methods of the study?
We were focussed mainly on progression free survival and response rate. It was a phase II randomised trial, one to one, so a patient could be assigned with the same probability to one arm or the other. Basically both main objectives, both progression free survival and response rate, were very similar in both but there was a small benefit with the use of cyclophosphamide. So pretty much the main conclusion we could say is that cyclophosphamide can be added to carfilzomib safely and there were no safety issues in that regard. It can be safely added to weekly carfilzomib, which is a kind of schedule we haven’t explored very much, but it’s unclear if it really adds something in terms of benefit. In any case, it does not add any toxicity, or any relevant toxicity.
What were the key results?
Probably the key result is the one that I just pointed out but probably the thing that caught the attention at ASH was the fact that there’s a subgroup of patients which are normally difficult to treat, which are lenalidomide refractory patients, that did quite better with the addition of cyclophosphamide than without the addition of cyclophosphamide. So even though the global results were that both arms were very similar, in this particular subgroup of patients, which is of special interest because it’s a really unmet medical need, the addition of cyclophosphamide doubled the time to progression which means quite a big impact. Of course, this should be confirmed in a larger trial. This is a phase II trial and we are talking about a subgroup of patients into that trial that showed an important benefit so we should just find this cohort of patients in a phase III trial just to confirm the results.
How does this research impact the future of multiple myeloma treatment?
There is one immediate impact, it’s the fact that in many countries, including most European countries, carfilzomib is not yet approved in combination with other drugs. So we don’t like very much doing carfilzomib and dexamethasone alone, we like to combine these two agents with another agent but we don’t have approvals for that yet. At least, outside lenalidomide we don’t have other approvals. So the addition of cyclophosphamide, which can be done and can be used, is probably beneficial in a subgroup of patients. So we can use a triple combination in a situation in which we have approvals for the doublet. That’s an immediate consequence of the trial.
Another, probably more important from a scientific point of view, is the fact that we should explore if in that subgroup of patients, the patients that I mentioned before, those patients that are not responding to lenalidomide, we could really improve their prognosis by the addition of cyclophosphamide to carfilzomib. So if we confirm these results in a larger trial then that can have important implications because we would have a pretty good treatment which is considerably less expensive than newer treatments that are coming into the clinics.
Is there anything you’d like to add?
I think that there are several combinations, very good several combinations, that are coming into the clinic in the relapsed refractory setting, particularly if we are talking about carfilzomib – carfilzomib in combination with daratumumab or isatuximab – they look pretty well. But in any case this combination that will be approved in Europe soon will be quite expensive and the addition of cyclophosphamide instead is a cheaper option that could be used throughout the world, even in less developed countries. So I think it’s a good hint of alternative treatments we could use.
In addition to that, we have to think that cyclophosphamide does not really impact toxicity very much so we could even think of more wide combinations even with cetuximab and daratumumab plus carfilzomib. But I would say that we have to be very cautious because the results of our trial may induce people to prescribe the combination of carfilzomib and cyclophosphamide in refractory patients, lenalidomide refractory patients, and I think that the results should be confirmed in a larger trial. So we have to be at least cautious with the results we’ve found.
