A treatment comparison of carfilzomib, dexamethasone and daratumumab to daratumumab and bortezomib

Prof Evangelos Terpos - University of Athens, Athens, Greece

This is a study which compared the CANDOR combination – carfilzomib given twice weekly at a dose of 56mg/m2, in combination with dexamethasone and daratumumab – versus the triplet of daratumumab, bortezomib and dexamethasone, the CASTOR first part of the study, daratumumab, Velcade and dexamethasone, and we tried to have a matching-adjusted daratumumab comparison because we wanted to know if dara-Kd or dara-Vd, the combination of daratumumab dexamethasone plus a proteasome inhibitor, either carfilzomib or bortezomib, can give indirect treatment comparison results to help the physicians to better use one of the two PIs in combination with daratumumab plus dexamethasone.

What were the results of the study?

First of all, we used a matching-adjusted indirect treatment comparison, as I previously mentioned, for the dara-Kd and dara-Vd patients who were matched for observed baseline characteristics in order to check the more important safety and efficacy results. Regarding efficacy, compared with daratumumab, Velcade and dexamethasone, it seems that treatment with daratumumab, carfilzomib and dexamethasone reduces the risk of progression or death by 39% overall and by 64% after eight cycles. The estimated PFS for the dara-Kd versus dara-Vd was 73% versus 60% at 12 months and 65.5% versus 47% at 18 months. So I think that this is one first important result.

Another important issue is what’s happening after eight cycles in bortezomib exposed patients. We have seen that in bortezomib exposed patients the dara-Kd reduces the risk of progression or death by 54% overall and 65% after eight cycles compared to dara-Vd. So, again, the estimated PFS was at 18 months 65% for dara-Kd versus 38% for daratumumab Velcade and dexamethasone.

Another important issue was the lenalidomide refractory subgroups. The PFS was more favourable with dara-Kd, like in the CANDOR study, versus dara-Vd and in lenalidomide refractory patients, where we had 54 in dara-Kd and 60 in dara-Vd, the overall hazard ratio was 0.28 in favour of dara-Kd. Just to give you a percentage at 18 months for lenalidomide refractory patients, the PFS probability at 18 months was 74% for dara-Kd and only 24.5% for dara-Vd.

What impact can these results have on the treatment of multiple myeloma?

This analysis suggests that a combination of daratumumab with carfilzomib and dexamethasone until progression improves the outcome compared to daratumumab Velcade and dexamethasone. But just keep in mind here that bortezomib was given for eight cycles in patients with relapsed refractory multiple myeloma who had received 1-3 prior lines of treatment. In terms of the results highlighted, carfilzomib is an effective combination partner with daratumumab, providing the rationale for the use of dara-Kd as a preferred regimen, especially in lenalidomide refractory patients.

However, we have to say that we do have limitations in the study because although this approach is in accordance with methods guidance, the matching-adjusted results are associated with incorrect limitations due to the decreased sample size for dara-Kd and due to known differences such as longer follow-up for the dara-Vd study or unobserved differences in the trials because we compare in such a way the results of two different trials. However, I have to say that this is the best methodology in order to be able to make such comparisons.

So, in total, I believe that this study may help the physicians to use dara-Kd versus dara-Vd for their better PI treatment in combination with daratumumab and dexamethasone, possibly carfilzomib is a better addition to daratumumab and dexamethasone and I would say especially for the lenalidomide refractory patients which is a really poor risk group.