Adding daratumumab to VRd shows better efficacy outcomes compared to VRd alone in multiple myeloma

Prof Pieter Sonneveld - Erasmus MC Cancer Institute, Rotterdam, Netherlands

We studied in newly-diagnosed patients with multiple myeloma the effect of a new regimen for induction, consolidation and maintenance using daratumumab, which is an anti-CD38 antibody, added to standard combination therapy consisting of VRd. In this study a couple of things were new. First, that it was a quadruplet regimen compared with a triplet regimen which is the current standard. Then, daratumumab was given subcutaneously, which is different from most previous trials, making it more easy for the patient. Then we also studied daratumumab in the maintenance phase of the treatment, so adding daratumumab to standard lenalidomide. There was a special question: if the study patients, they are in CR for two years and they are MRD, minimal residual disease, negative for at least a year, can we then stop daratumumab and continue with lenalidomide?

What were the results?

The primary endpoint of the study was progression free survival, and this was highly significant. The difference at a follow-up of four years was 84% PFS in the daratumumab treated patients compared to 67 in the VRd only treated patients. The hazard ratio was 0.42  which is almost unprecedented in a large phase III trial in newly-diagnosed multiple myeloma. So there is a 58% reduction of progression or death, and this was observed across all pre-specified subgroups, also cytogenetics. The secondary endpoint was complete response rate or better and also this was highly superior in the patients where they were treated with daratumumab plus VRd compared to VRd alone. The overall CR or better rate was 87% compared to 70% in the control arm, again across all different subgroups.

Then another secondary endpoint which we consider very important is the minimal residual disease negativity rate. This is probably going to be a future endpoint of response. We observed MRD negativity at 10-5 and 10-6 in these patients. So if we take, for example, 10-6, the MRD negativity rate was 65% compared with 32% in the control arm. Also sustained MRD negativity, so continuous MRD negativity for at least 12 months, was highly significantly different in favour of the daratumumab + VRd arm, indicating that also at the most sensitive parameters of response we observe a deeper effect of treatment with daratumumab plus VRd.

So overall we see an increase of MRD negativity rates over time in individual patients from initial treatment to consolidation to overall during maintenance, which is consistent and will hopefully last for a longer time. But this has to be evaluated later when we have a longer follow-up.

So the conclusions are that daratumumab + VRd results in a better progression free survival, with a hazard ratio of 0.42, and it’s a better CR rate and a higher overall MRD negativity rate.

The safety profile, which I did not mention yet, was also consistent with the already known safety profile for both daratumumab subcutaneous and VRd separately, so there’s no safety concern. We think that based on these results daratumumab + VRd followed by daratumumab plus lenalidomide maintenance should be a new standard of care for transplant-eligible patients with newly-diagnosed multiple myeloma.

I would like to thank all the collaborators in this study. The full article of this trial can be found in The New England Journal of Medicine in the issue of December 2023.