Daratumumab-VTd Regimen Shows Benefit in Newly Diagnosed High-Risk Multiple Myeloma

Tony Berberabe, MPH @OncBiz_Wiz
Published: Saturday, Sep 14, 2019

Pieter Sonneveld, MD, PhD, professor of hematology and head of the Department of Hematology at Erasmus MC Cancer Institute in The Netherlands

Pieter Sonneveld, MD, PhD

The regimen of daratumumab (Darzalex), bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (D-VTd) demonstrated an improvement in minimal residual disease (MRD) negativity rates and progression-free survival (PFS) compared with VTd alone in patients with high-risk multiple myeloma, according to a subgroup analysis of the phase III CASSIOPEIA trial.1

The phase III CASSIOPEIA trial randomized 1085 treatment-naïve, transplant-eligible patients with multiple myeloma who were transplant eligible to receive the daratumumab regimen or VTd alone.

The trial was divided into 2 parts, an induction and consolidation phase, followed by a maintenance treatment with daratumumab or observation. Findings for part 1 of the study demonstrated a 53% reduction in the risk of progression or death in the D-VTd arm versus VTd alone (HR, 0.47; 95% CI, 0.33-0.67; P <.0001).2

The subgroup analysis data, which were presented at the 17th International Myeloma Workshop, showed that D-VTd led to a 34% reduction in the risk of disease progression or death compared with VTd alone in those with International Staging System (ISS) Stage III disease (HR, 0.66; 95% CI, 0.32-1.39). In patients with high-risk cytogenetics of del(17p) or t(4;14), the daratumumab regimen reduced the risk of disease progression or death by 33% (HR, 0.67; 95% CI, 0.35-1.30).

However, a benefit with stringent complete response rate was not observed with D-VTd over VTD alone in those with ISS Stage III disease (P = .8506) or high-risk cytogenetics (P = .4839).

In May 2019, the FDA granted a priority review designation to a supplemental biologics license application for D-VTd for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant, based on part 1 of the phase III CASSIOPEIA trial. The FDA is scheduled to make a decision on the application on or before September 26, 2019.

In an interview with OncLive during the 17th International Myeloma Workshop, lead author Pieter Sonneveld, MD, PhD, professor of hematology and head of the Department of Hematology at Erasmus MC Cancer Institute in The Netherlands, discussed the significance of the subgroup analysis.

OncLive: Could you discuss the results of your subgroups analysis?

Sonneveld: We presented a subgroup analysis, which was a planned analysis, for the outcomes in patients with high-risk disease. This is for patients with ISS Stage III or with high-risk cytogenetics: del(17p) and t(4;14). Of course, this is a small subgroup. However, we were able to analyze the data and the results indicate that the response rate is the same in these high-risk cytogenetics and ISS Stage III as compared with the intent-to-treat population—so the full population.

Of 1085 patients randomized to D-VTd or VTd, 15.5% had a high-risk cytogenetic abnormality. ISS staging was 39.8%, 45.0%, and 15.2% for stage I, II, and III, with more patients classified as stage II in D-VTd versus VTd and similar patients classified as stage III in D-VTd versus VTd.

Another issue fully addressed in this trial was the MRD negativity. For the first time, in a frontline trial in transplant-eligible patients, we conducted a full analysis of MRD using flow cytometry. The results are published, but it’s important to note that MRD negativity was achieved in about 64% of patients with D-VTd. This is a significant increase of MRD negativity.

The MRD-negative rate was higher for D-VTd versus VTd, including in high-risk cytogenetic and ISS stage III subgroups. We also looked at PFS. With a follow-up time of only 18 months, we see the curves are going to separate and that there is significant benefit for D-VTd in this high-risk subgroup.

How would you define the significance of the data in terms of cytogenetic risk and ISS stage?

For patients who were ISS Stage III or had high-risk cytogenetics, we see a benefit for D-VTd over VTd alone. These smaller number of patients represent less than 10% of total patients. We can’t draw firm conclusions right now, but we can see that response rate, the level of MRD negativity, and PFS are of the same order of magnitude as in the intent-to-treat population.

How do these findings inform current thinking about treating patients with multiple myeloma?

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