DREAMM-3 - Blenrep (Belmaf) vs. PomDex for Relapsed/Refratory Myeloma | Katja Weisel, MD | ASCO 2023

Hello, my name is Katja Weisel. I'm from the University Medical Center in Hamburg-Eppendorf in Hamburg in Germany. And I'm happy to be here at the ESCO 2023 in Chicago. And I presented on behalf of my co-authors here the results of an international phase three approval trial, the Dream3 trial. And the Dream3 trial is designed for patients with relapsed multiple myeloma disease who had at least two prior treatment lines. And it compared in a randomized fashion the monotherapy with the antibody drug conjugate, belantamathmaphodotin, or we call it Belamath, which is against BCMA-directed, against the standard of care with pomalidomide and dexamethasone, which is widely approved for treatment of relapsed myeloma all over the world. So we had kind of a head-to-head comparison of two totally different drugs or regimens for relapsed myeloma disease. The trial included 325 patients and there was a two-to-one randomization so that two-thirds of the patients received belantamathmaphodotin, which was replicated in a half an hour infusion every three weeks. No dexamethasone added, nothing added, so pure monotherapy. And one-third of the patients were assigned to pomalidomide and dexamethasone in the well-known four-week cycle regimen. And the primary endpoint of this trial was progression-free survival, so as in the most myeloma trials the primary endpoint is. Secondary endpoints were overall survival, also life quality and others. The presentation yesterday focused on the presentation of the primary endpoint. Let's look first about the patients who were included into the trial. The median age was 68 overall, a better and elderly population than in other trials investigating immunotherapies against BCMA. And we had about 20 percent triple refractory patients, so patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a monoclonal anti-CD38 antibody. The primary endpoint analysis showed that the median progression-free survival was longer for belantamathmaphodotin with 11.2 months compared to 7.0 with pomalidomide and dexamethasone. However, as you probably heard, the trial did not reach statistical significance and in fact the drug was taken off the market in the U.S. after the results were published. So why did that happen when there was more than a four-month benefit in progression-free survival? This happened because the Kaplan-Meier curves were crossing after four months, and so that we had more early progressions on the monotherapy compared to pomalidomide, dexamethasone as a doublet, and especially the dexamethasone might here lead to an initially bit greater disease control. However, after crossing, the Bellarmuff arm stayed superior and stably superior to pomdex, so that with the longer follow-up, the trial might gain against statistical significance. However, currently we could not see that. But there is a unique feature of Bellantamaphodotin, which is the immunogenic effects of the drug, and that is reflected in the duration of response. Patients who responded to Bellantamaphodotin had a very long-lasting durability of the response, and the median duration of response was not reached at the time of analysis, and here we had a very clear separation of the curves. In overall survival, there was not a mature analysis, but there were similar results between both arms. Regarding side effects, we know that Bellantamaphodotin can do a distinct ocular toxicity. However, we also know that this is reversible. Bilateral worsening in visual acuity occurred in some patients, but only in two patients in a severe manner. The median time that this happens is about two months after initiation of treatment, and it's then after about four to six weeks, again reversible. However, comparing the toxicity of both regimens, we saw that Bellamaphodotin led to a lower rate of neutropenia, especially severe neutropenia, and we had a very low rate of infections. The grade 3 for infection rate was 13 percent and about half in the pomdex arm. Regarding the patient-reported outcomes, we saw that in both arms about 70 percent of patients felt not bothered by the treatment, and we had an improvement in global health status in both treatment arms, especially at later time points. Bellamaph was superior to pomalidomide and dexamethasone in regards of fatigue. There was a more favorable development than in the pomdex arm. So what can we draw as conclusions out of this trial? We see overall we have unfortunately a negative study. However, we see that a monotherapy without dexamethasone is at least as effective as a dexamethasone-containing doublet, and it's the only any BCMA-directed agent currently on the market, which is broadly available, which has no limitations in availability, as CAR T cells do have, or also the bi-specific antibodies. We have a favorable safety profile as we also learn to deal with the ocular toxicity now, knowing that it's reversible, that there is eye protection possible. We see that not enough patients are responding to Bellamaph initially. This was the reason for the steep and early drop of the Kaplan-Meier curve. So it should be our goal to figure out how to make the drug more effective from the beginning, and that might be combinations. And there are a few combination studies underway, for example, Dream 7 and Dream 8, where we expect a readout in the next year. So that I hope that we learn with all those trials where the drug really fits in for you as patients, and who most benefit from Bellantham atmaphodotin, which is still an important gain in our treatment armamentarium in a global view.