In an interview with _Pharmacy Times®,_ Sonja Zweegman, MD, PhD, professor of hematology at Amsterdam University Medical Center, discussed her presentation on new data from the CEPHEUS trial, which demonstrated that the addition of daratumumab (dara) to VRd significantly increased MRD negativity rates compared to bortezomib, lenalidomide, and dexamethasone (VRd) alone in patients with newly-diagnosed multiple myeloma (NDMM) who are transplant-ineligible or transplant-deferred. The regimen was strongly associated with sustained minimum residual disease negativity and improvements in overall survival compared with the VRd regimen alone.
Zweegman elaborates on the clinical implications for the significantly improved depth and duration of MRD negativity in transplant-ineligible or transplant-deferred patients with NDMM, and explains how the combination may be further effective in other patient populations.
**_Pharmacy Times:_** What are the key points of the CEPHEUS trial regarding long-term disease control and overall survival?
**Sonja Zweegman:** The CEPHEUS trial was a trial for newly-diagnosed multiple myeloma patients who were not eligible for stem cell transplantation (SCT), or in whom a SCT was deferred. Three hundred ninety-five patients were randomized between either bortezomib (Velcade; Takeda Pharmaceuticals), lenalidomide, and dexamethasone (VRd) for 8 cycles, followed by len-dex until progression, or daratumumab (dara) added to VRd, and then, after 8 cycles, continuation of the therapy with dara/len-dex. That resulted in a superior progression free survival. There was a 43% risk reduction in progression or death after the addition of daratumumab to VRd. We presented actually a more detailed analysis on minimal residual disease (MRD) negativity, so MRD-negative complete response (CR). That was also the primary end point of the study, and we showed that there was a 50% increase in reaching MRD negativity.
Now, into detail, the cumulative incidence of MRD negativity increased over time. The MRD CR-negative rates were obtained faster, they were deeper, and they continued to increase over time in the VRd arm until approximately 3 years. It seems that in the dara-VRd arm there's a continuous increase over time further than 3 years. Also, the sustained MRD negativity rates were doubled. After more than 12, 24, or 36 months, the addition of dara led to a doubling of the sustained MRD negativity. That paves the way for quadruple therapy, also for older patients with multiple myeloma who are not transplant eligible, because the high rate of MRD negativity and the deep MRD-negative CR rates led to a very good medium progression free survival. Those patients who were treated with dara-VRd and obtained MRD negativity until the 10\-6, more than 85% of the patients were still without progression and alive after 45 months. I think that's very good results, and again, that should lead to the implementation of quadruple therapy, also for all the patients with multiple myeloma, perfect.
**_Pharmacy Times:_** Are there specific patient populations beyond the one focused on in CEPHEUS that may benefit from D-VRd therapy?
**Zweegman:** Importantly, in this trial, frail patients were not included, and we know that many patients who are non-transplant eligible are frail. It will be interesting to have a look whether frail patients can also benefit from quadruple therapy and, well, the jury is not out yet, so we'll have to investigate it for future.