Daratumumab-Based Quadruplet Demonstrates Efficacy in High-Risk Myeloma Subgroups

Pieter Sonneveld, MD, PhD

Daratumumab (Darzalex) in combination with bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (D-VTd) demonstrated benefit compared with VTd alone in subgroup analyses of patients with high-risk multiple myeloma from the phase III CASSIOPEIA trial.¹

The phase III CASSIOPEIA trial randomized 1085 treatment-na&iuml;ve, 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 withTargeted Oncologyduring 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.

TARGETED ONCOLOGY: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 minimal residual disease (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&rsquo;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 progression-free survival (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.

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

Sonneveld: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&rsquo;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.

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

Sonneveld:We think that not only for the high-risk patients, but for the whole group of patients who are transplant-eligible and newly diagnosed with myeloma, that there will be a new standard in the future coming from VTd, or the regimen of bortezomib, lenalidomide (Revlimid), dexamethasone (VRd), or other triple-drug combinations going to a 4-drug regimen, including daratumumab, will eventually become the new standard of treatment.

It&rsquo;s too early to do that right now because we are waiting for the results of the second randomized part of the study that involves daratumumab as a maintenance therapy. However, based on the first part of the trial, we have submitted data to the regulatory bodies. My assumption is that, like in the older patients, adding daratumumab will become a standard for the initial treatment of patients.

TARGETED ONCOLOGY:What impact could the combination of daratumumab and VTd have on the community oncologist if it is approved?

Sonneveld:The big question is whether we will have approval to use daratumumab in the first-line setting, not only in the elderly, but also in the transplant-eligible patients.

Once the combination [is approved] it offers the unique opportunity for a high response rate, for long-term PFS. Therefore, I expect that it will be popular in the community setting. Patients will enjoy a long disease-free period, with a good quality of life—maybe going back to work and enjoying life&mdash;which is important. Daratumumab adds to the common standard of treatment.

TARGETED ONCOLOGY:Did the study findings strengthen the case for finding the right combination of treatments?

Sonneveld:This is one of the new options. Currently, we are running another study in the European Myeloma Network of D-VRd, which is highly comparable with the CASSIOPEIA trial. However, VRd is a more effective regimen than VTd. We consider this an upgrade of the original treatment with daratumumab.

Also, other combinations are undergoing investigation including isatuximab, which is another CD38-directed antibody [in] the ICARIA-MM study in the relapsed setting.

We probably have a new standard here, from diagnosis through the different stages of the disease and treatment.

TARGETED ONCOLOGY:What are the next steps with this research?​​​​​​​

Sonneveld:We need to look closer at the issue of retreatment. If we treat patients upfront with daratumumab, at a certain stage they will stop their treatment. If they progress or relapse, can we treat them again with daratumumab to the full benefit of the drug? Or, should we switch to another antibody like isatuximab or elotuzumab (Empliciti)? There are many others.

Then, the important issue is that we treat as many patients [as we can] with daratumumab in the first-line setting. This is the priority. The relapsed setting is also a valuable place for daratumumab, but it should not be our first goal. What we don&rsquo;t know yet is how this treatment compares with other [monoclonal antibodies] and if we can combine with other [monoclonal antibodies].

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References

1. Sonneveld P, Attal M, Perrot A, et al. Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (NDMM): subgroup analysis of high-risk patients (Pts) in CASSIOPEIA. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract OAB-003.
2. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.Lancet.2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.