Monoclonal Antibody Therapy in the Frontline for Multiple Myeloma

Saad Z. Usmani, MD, FACP:There is a strong rationale to combine monoclonal antibodies in the frontline setting for transplant-ineligible patients. The reason being that]monoclonal antibodies generally tend to have minimal adverse effects—short term and long term—and they generally do not overlap with the adverse effects from other drugs that you are thinking about combining them with. The best example for that would probably be the combination of daratumumab with VMP [bortezomib-melphalan-prednisone] in the frontline setting. The ALCYONE trial, which read out at the end of 2017, was presented as a late-breaking abstract and subsequently published in early parts of 2018. It was a large randomized phase III trial done in transplant-ineligible patients, where daratumumab-VMP [bortezomib-melphalan-prednisone] was compared with VMP [bortezomib-melphalan-prednisone], which is a standard-of-care therapy in Europe.

The results showed better depth of response in the experimental arm, with improvement in progression-free survival, which was the primary endpoint of the study. Improvement in the depth of response by MRD [minimal residual disease] negativity was measured at 10^-5with the NGS [next-generation sequencing] method. These results eventually led to the approval of this combination for frontline patients in the United States. I’ve already shared the data from an efficacy standpoint. From a safety standpoint in ALCYONE, there was a higher incidence of cytopenias and infections, specifically pneumonia. There were no other safety signals that were observed in that combination.

The POLLUX trial was a large randomized phase III trial that compared the combination of daratumumab-lenalidomide-dexamethasone with lenalidomide-dexamethasone in patients who had at least 1 prior line of treatment. This trial resulted back in 2016, leading to the approval of the combination of daratumumab-lenalidomide-dexamethasone in the first and beyond-relapse setting.

The interesting thing about the efficacy primary endpoint results was that, at the time the trial read out, the median PFS [progression-free survival] on the daratumumab-lenalidomide-dexamethasone arm had not been reached. Late last year, we reported on those data showing the median PFS being roughly a little over 44 months, which was quite impressive compared with what the median PFS had been reported for similar phase III studies, comparing 3-drug versus 2-drug combinations. One unique feature about the trial was that both of the arms continued therapy until relapse and progression, so it wasn’t a fixed duration question being asked. There was almost a 4-fold increase in MRD negativity in the 3-drug combination arm compared with the 2-drug combination arm. The overall response rate was roughly 93% versus 78% compared with the standard-of-care arm.

The experience in the POLLUX trial set the stage for a frontline trial with a similar design, looking at the combination of daratumumab-lenalidomide-dexamethasone versus lenalidomide-dexamethasone for transplant-ineligible patients. The study was designed as a 1:1 randomization of an experimental versus standard-of-care arm. The treatment was continued until relapse or progression in both arms. The primary endpoint for this study was median PFS. Important secondary endpoints were overall response rates, MRD negativity rates, as well as overall survival and duration of therapy.

It was interesting to see that the standard-of-care arm performed quite well. The median PFS was 31.9 months on the standard-of-care arm. Despite that, the experimental arm continued to do well, reaching its primary endpoint. This trial was presented as a late-breaking abstract at ASH [American Society of Hematology Annual Meeting & Exposition] in 2018. The overall response rates were quite impressive—in the mid-90s. MRD-negativity rates were almost 4-fold compared with the standard-of-care arm. Nothing new was observed compared with what had been seen in the POLLUX experience when looking at the safety signal. Cytopenias and a slightly higher rate of infections were observed in the daratumumab-lenalidomide-dexamethasone arm on the MAIA trial.

It is also important to note that the complete response or better rates were almost doubled in the experimental arm—47.6% versus a little over 24% in the standard-of-care arm. The median follow-up at the time the study was presented was 28 months. It is a little too early to see a difference in overall survival, and that is why the hazard ratio was about 0.78 at this follow-up time point.

The assessment of minimal residual disease has been readily incorporated in clinical trials over the past 5 years in the early relapsed setting as well as in the frontline setting. It has been correlated with overall survival benefit. Achieving MRD negativity, from a prognostic standpoint, helps us in identifying patients who are going to do exceptionally well with any given therapy.

At this point, we are not utilizing MRD results to modify treatment, but it does help inform us on what would be the best strategy to get patients to MRD negativity when they’re sitting in front of you and having that discussion. MAIA is 1 of the first frontline trials that has incorporated MRD assessments. ALCYONE was another frontline trial that incorporated MRD in the frontline setting. These results are showing us that the addition of a monoclonal antibody to available regimens improves the depth of response for patients.

Transcript edited for clarity.