I will present an abstract in which we are going to evaluate the efficacy of carfilzomib, a second generation proteasome inhibitor, used in at least three clinical trials in the relapsed and refractory setting in patients with myeloma after at least one prior line of therapy but with a special focus on patients who had been previously treated with lenalidomide and specifically patients that were refractory to lenalidomide.
What is the rationale of this abstract?
Carfilzomib is a second generation proteasome inhibitor more effective than bortezomib and it represents a standard of care to be used at the relapsed setting. It has been evaluated in three different clinical trials: in the ENDEAVOR study patients after one to three prior lines of therapy, kd [?] 56mg/m2 twice weekly; CHAMPION-1 study relapsed and refractory myeloma patients, one to three prior lines of therapy, and carfilzomib was given 70mg/m2 once weekly; and ARROW study, a phase III randomised trial conducted in relapsed and refractory myeloma patients after two to three prior lines of therapy, so late advanced stage of the disease, with carfilzomib 70mg/m2 also weekly and compared with 27mg/m2 twice weekly.
The main message is that in the ARROW study most patients had been exposed to lenalidomide and, in fact, most of them were lenalidomide refractory. In the CHAMPION-1 study also approximately 50% of patients were previously exposed to lenalidomide and more than 60% were lenalidomide refractory. In the ENDEAVOR, so this is the large randomised trial, I would say that approximately 30% of patients were lenalidomide exposed and approximately 50% of them were refractory to lenalidomide.
Lenalidomide is becoming a standard of care in the first line of therapy for patients with multiple myeloma so one appropriate question that we wanted to address in this abstract is if carfilzomib is a potential option to rescue these patients after lenalidomide as continuous therapy, so patients are going to be lenalidomide refractory. The answer is yes – when we evaluated the median progression free survival in all these trials in patients exposed to lenalidomide the median PFS was approximately 16 months. When we evaluated the median PFS in patients refractory to lenalidomide as part of the first line of therapy and treated with carfilzomib in the different trials at first relapse the median progression free survival was maintained and was 15.6 months. This is important because these results are in line with other studies in which novel combinations have been also evaluated in the context of lenalidomide refractory patients. When we evaluated the overall series of patients and we put together all lenalidomide refractory patients the median progression free survival for carfilzomib as rescue therapy was 9 months which is also consistent with other novel agents evaluated in the same population.
The overall response rate in lenalidomide exposed and lenalidomide refractory is also on line, approximately 80-85% of the patients exposed to lenalidomide and refractory to lenalidomide as part of the first line of therapy was 85% when they received carfilzomib at first relapse. When we moved to the late advanced stage of the disease the overall response rate is approximately 60-62%.
So the conclusion of this abstract is that if we consider that we can potentially use carfilzomib as rescue therapy in patients previously treated with lenalidomide and refractory to lenalidomide the answer is clearly yes. We are going to switch drug class because we are going to move to a proteasome inhibitor more potent than the first generation proteasome inhibitor bortezomib. I think that it is safe and effective in this specific patient population.
In addition, the next step would be to add a monoclonal antibody to carfilzomib and we have some preliminary data in these lenalidomide refractory patients adding the CD38 monoclonal antibody daratumumab to carfilzomib and dexamethasone in lenalidomide refractory myeloma patients and the median progression free survival is also very long – longer than 16 months. So definitely carfilzomib is an option to rescue patients previously treated and refractory to lenalidomide.
What about the toxicity profile of carfilzomib?
Carfilzomib, we know very well the toxicity profile of carfilzomib and in all these studies it is reported haematological toxicity, especially thrombocytopenia grade 3/4 occurring in no more than 20-25% of patients, manageable and not associated with significant bleeding. From the non-haematological point of view the toxicity is acceptable; we have to take care with hypertension because some patients with a prior history of hypertension have to be very well controlled before starting treatment with carfilzomib otherwise we can have some problems because hypertension has been reported in the different studies in a proportion of patients, about 10-15%. But with this exception, so to take care about hypertension, I would say that the toxicity profile is acceptable and we have not to take care about any other specific toxicity.
Is this something that could be incorporated into everyday practise?
From the practise point of view when we have in front of us patients at first or second relapse that they have previously received lenalidomide and as lenalidomide is given as continuous therapy patients are refractory to lenalidomide and the question is how to proceed. Is it appropriate to switch drug class and to go to carfilzomib and dexamethasone as in the ENDEAVOR, 56 mg/m2 twice weekly or 70mg/m2 once weekly? The answer is clearly yes and, as I previously said, the next step would be to combine carfilzomib and dexamethasone plus the monoclonal antibody.