CANDOR: Triple drug combo delays disease progression in stubborn multiple myeloma
Dr Saad Usmani - Levine Cancer Institute, Charlotte, USA
In terms of the background for the phase III CANDOR study the clinical context is important. Of the six options we have in this setting four contain lenalidomide as part of the triplet regimen. The clinical practice currently, many patients receive lenalidomide as part of maintenance treatment so they’re either lenalidomide exposed or relapsing or are getting refractory to lenalidomide and then progressing. So options for those patients tend to be a little bit more limited than patients who are lenalidomide naïve or lenalidomide sensitive. With that context in mind the CANDOR trial is important. It compares carfilzomib, dexamethasone and daratumumab to carfilzomib dexamethasone in one to three prior lines of treatment patients.
The study design was a two-to-one randomisation schema. For every one patient receiving carfilzomib dexamethasone two patients were randomised to receive the combination of daratumumab with carfilzomib dexamethasone. There were a total of 466 patients that were randomised to the study. The key features were one to three prior lines of treatment; patients with prior bortezomib or lenalidomide exposure or even lenalidomide refractory status were allowed to come on study. Patients who had received prior carfilzomib or daratumumab were also allowed to come on study as long as patients had not received those drugs in the past six months and had at least a partial response to those treatments. Treatment was continued until relapse, progression or intolerance. The primary endpoint for the study was progression free survival and important other secondary endpoints were overall survival, overall response rate, MRD negative CR rates at twelve months, safety profile, so treatment emergent adverse events, and such.
After a median follow-up of 17 months the primary endpoint for the study was met. The KD arm had a median PFS of 15.8 months and the median PFS on the daratumumab KD arm was not met with a hazard ratio of 0.63. The overall response rate was higher at 84% versus 73%. The MRD negative CR rate at twelve months was 12.5% versus 1.3%. All of these things were in favour of the three drug combination. At the median follow-up of 17 months there were no differences between the median overall survival.
Safety profile wise the grade 3 or higher adverse events were higher in the three drug combination and most of those events, most of the difference came from the incidence of infection. So higher incidence of infections were observed in the daratumumab KD arm. We’ve seen this signal with other carfilzomib and daratumumab based regimens so this is a known AE to us. But what was interesting is that the daratumumab KD arm had a lower incidence of grade 3 or higher cardiac failure rates which was a little surprising because this is a little bit of a concern with carfilzomib based regimens. So seeing those rates, low rates, was interesting.
Even though there were no differences in the median overall survival at the 17 month time-point, there were five treatment emergent fatal AEs on the KD daratumumab arm whereas on the KD arm there were zero. Of those five events, four appeared to be infection related with sepsis, septic shock as well as pneumonia.
So bearing in mind that all the pre-specified subgroups also had the benefit, including the lenalidomide exposed and lenalidomide refractory patients, these results are important based on efficacy as well as the safety profile taken together. This is a good three drug, IMiD free regimen that will be a good option for lenalidomide exposed or lenalidomide refractory patients.